Methyl α-(2-substituted)pyrid-3-yl-β-methoxyacrylates, compositions containing them and their use as fungicides

ABSTRACT

Fungicidal compounds of the formula (I): ##STR1## and stereoisomers thereof, wherein K is oxygen or sulphur; Z is optionally substituted aryl or optionally substituted heteroaryl; X is O, S(O) n , NR 4 , CR 1  R 2 , CHR 5 , CO, CR 1  (OR 2 ), C═CR 1  R 2 , CHR 1  CHR 2 , CR 1  ═CR 2 , CHR 1  CR 2  ═CH, C═C, OCHR 1 , CHR 1  O, OCHR 1  O, S(O) n  CHR 1 , S(O) n  CHR 1  O, CHR 1  S(O) n , CHR 1  OSO 2 , NR 4  CHR 1 , CHR 1  NR 4 , CO 2 , O 2  C, SO 2  O, OSO 2 , CO.CO, COCHR 1 , COCHR 1  O, CHR 1  CO, CHOH.CHR 1 , CHR 1 .CHOH, ##STR2## CONR 4 , OCONR 4 , NR 4  CO, CSNR 4 , OCS.NR 4 , SCO.NR 4 , NR 4  CO 2 , NR 4  CS, NR 4  CSO, NR 4  COS, NR 4  CONR 4 , S(O) n  NR 4 , NR 4  S(O) n , CS 2 , S 2  C, CO.S, SCO, N═N, N═CR 1 , CR 1  ═N, CHR 1  CHR 2  CH(OH), CHR 1  OCO, CHR 1  SCO, CHR 1  NR 4  CO, CHR 1  NR 4  COR 4 , CHR 1  CHR 2  CO, O.N═CR 1 , CHR 1  O.N═CR 2 , CO.OCR 1  R 2 , CHR 1  CHR 2  CHR 3 , OCHR 1  CHR 2 , (CH 2 ) m  O, CHR 1  OCHR 2 , CHR 1  CHR 2  O, OCHR 1  CHR 2  O, S(O) n  CHR 1  CHR 2 , CHR 1  S(O) n  CHR 2 , CHR 1  CHR 2  S(O) n , CR 1  ═NNR 4 , NR 4  N═CR 1 , CHR 1  CONR 2 , CHR 1  OCO.NR 2 , CH═CHCH 2  O, COCHR 1  CHR 2  O or (R 5 ) 2  P.sup. + CHR 2  Q -  ; A, B and E, which may be the same or different, are H, hydroxy, halo, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  alkylcarbonyl, C 1-4  alkoxycarbonyl, phenoxy, nitro or cyano; R 1 , R 2  and R 3 , which may be the same or different, are H, C 1-4  alkyl or phenyl; R 4  is H, C 1-4  alkyl or COR 1  ; R 5  is optionally substituted phenyl; Q -   is a halide anion; n is 0, 1, or 2 and m is a 3, 4 or 5.

This is a continuation of application Ser. No. 07/258,742, filed Oct.17, 1988, now U.S. Pat. No. 5,008,276 which is a continuation-in-part ofSer. No. 039,401, filed Apr. 17, 1987, now U.S. Pat. No. 4,826,531.

This invention relates to derivatives of propenoic acid useful asfungicides, to processes for preparing them, to fungicidal compositionscontaining them, and to methods of using them to combat fungi,especially fungal infections of plants.

The present invention provides a compound having the formula (I);##STR3## and stereoisomers thereof, wherein K is oxygen or sulphur; Z isoptionally substituted aryl or optionally substituted heteroaryl; X isO, S(O)_(n), NR⁴, CR¹ R², CHR⁵, CO, CR¹ (OR²), C═CR¹ R², CHR¹ CHR², CR¹═CR², CHR¹ CR² ═CH, C═C, OCHR¹, CHR¹ O, OCHR¹ O, S(O)_(n) CHR¹, S(O)_(n)CHR¹ O, CHR¹ S(O)_(n), CHR¹ OSO₂, NR⁴ CHR¹, CHR¹ NR⁴, CO₂, O₂ C, SO₂ O,OSO₂, CO.CO, COCHR¹, COCHR¹ O, CHR¹ CO, CHOH.CHR¹, CHR¹.CHOH, ##STR4##CONR⁴, OCONR⁴, NR⁴ CO, CSNR⁴, OCS.NR⁴, SCO.NR⁴, NR⁴ CO₂, NR⁴ CS, NR⁴CSO, NR⁴ COS, NR⁴ CONR⁴, S(O)_(n) NR⁴, NR⁴ S(O)_(n), CS₂, S₂ C, CO.S,SCO, N═N, N═CR¹, CR¹ ═N, CHR¹ CHR² CH(OH), CHR¹ OCO, CHR¹ SCO, CHR¹ NR⁴CO, CHR¹ NR⁴ CONR⁴, CHR¹ CHR² CO, O.N═CR¹, CHR¹ O.N═CR², CO.OCR¹ R²,CHR¹ CHR² CHR³, OCHR¹ CHR², (CH₂)_(m) O, CHR¹ OCHR², CHR¹ CHR² O, OCHR¹CHR² O, S(O)_(n) CHR¹ CHR², CHR¹ S(O)_(n) CHR², CHR¹ CHR² S(O)_(n), CR¹═NNR⁴, NR⁴ N═CR¹, CHR¹ CONR², CHR¹ OCO.NR², CH═CHCH₂ O, COCHR¹ CHR² O,or (R⁵)₂ P^(') CHR² Q⁻ ; A, B and E, which may be the same or differentare H, hydroxy, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, phenoxy, nitro orcyano; R¹, R² and R³ , which may be the same or different, are H, C₁₋₄alkyl or phenyl; R⁴ is H, C₁₋₄ alkyl or COR¹ ; R⁵ is optionallysubstituted phenyl; Q⁻ is a halide anion; n is 0, 1 or 2 and m is 3, 4or 5.

Of particular interest are those compounds in which X is O, OCH₂, CH₂ O,and SO₂ O.

The compounds of the invention contain at least one carbon-carbon doublebond, and are sometimes obtained in the form of mixtures of geometricisomers. However, these mixtures can be separated into individualisomers, and this invention embraces such isomers, and mixtures thereofin all proportions including those which consist substantially of the(Z)-isomer and those which consist substantially of the (E)-isomer.

The individual isomers which result from the unsymmetrically substituteddouble bond of the propenoate group are identified by the commonly usedterms "E" and "Z". These terms are defined according to the Cahn-Ingold-Prelog system which is fully described in the literature (see,for example, J March, "Advanced Organic Chemistry", 3rd edition,Wiley-Interscience, page 109 et seq).

Usually one isomer is more active fungicidally than the other, the moreactive isomer usually being the one wherein the groups --CO₂ CH₃ and--OCH₃ are on opposite sides of the olefinic bond of the propenoategroup (the (E)-isomer). These (E)-isomers form a preferred embodiment ofthe invention.

The substituent Z in compound (I) is optionally substituted aryl oroptionally substituted heteroaryl. Where valency allows, each of theoptionally substituted groups aryl or heteroaryl can carry up to 5substitutents. The term "aryl" includes phenyl in particular, andnaphthyl. The term "heteroaryl" includes 5- and 6-membered heterocyclicgroups containing one or more of each of the heteroatoms O, S and N(preferably S or N), fused benzenoid and heteroaromatic ring systems,and, in each case, the corresponding N-oxides. Examples of heteroarylgroups which Z may be are pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, 1,2,3-, 1,2,4-, and 1,3,5-triazinyl, 1,2,4,5-tetrazinyl,1,2,3- and 1,2,4-trizolyl, thienyl, furyl, pyrrolyl, thiazolyl,oxadiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothienyl,benzoxazolyl and benzthiazolyl and, where appropriate, the correspondingN-oxides. Substituents which may be present in the optionallysubstituted aryl and heteroaryl moieties include one or more of thefollowing; halo, hydroxy, mercapto, C₁₋₄ alkyl (especially methyl andethyl), C₂₋₄ alkenyl (especially allyl), C₂₋₄ alkynyl (especiallypropargyl), C₁₋₄ alkoxy (especially methoxy), C₂₋₄ alkenyloxy(especially allyloxy), C₂₋₄ alkynyloxy (especially propargyloxy),halo(C₂₋₄)alkyl (especially trifluoromethyl), halo(C₁₋₄)alkoxy(especially trifluoromethoxy), C₁₋₄ alkylthio (especially methylthio),hydroxy(C₁₋₄)alkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, optionally substituted aryl (especiallyoptionally substituted phenyl), optionally substituted heteroaryl(especially optionally substituted pyridinyl or pyrimidinyl), optionallysubstituted aryloxy (especially optionally substituted phenoxy),optionally substituted heteroaryloxy (especially optionally substitutedpyridinyloxy or pyrimidinyloxy), optionally substituted aryl(C₁₋₄)alkyl(especially optionally substituted benzyl, optionally substitutedphenethyl and optionally substituted phenyl n-propyl) in which the alkylmoiety is optionally substituted with hydroxy, optionally substitutedheteroaryl(C₁₋₄)alkyl (especially optionally substituted pyridinyl- orpyrimidinyl(C₁₋₄)alkyl), optionally substituted aryl(C₂₋₄)alkenyl(especially optionally substituted phenylethenyl), optionallysubstituted heteroaryl(C₂₋₄)alkenyl (especially optionally substitutedpyridinylethenyl or pyrimidinylethenyl), optionally substitutedaryl(C₁₋₄)alkoxy (especially optionally substituted benzyloxy),optionally substituted heteroaryl(C₁₋₄)alkoxy (especially optionallysubstituted pyridinyl- or pyrimidinyl(C₁₋₄)alkoxy), optionallysubstituted aryloxy(C₁₋₄)alkyl (especially phenoxymethyl), optionallysubstituted heteroaryloxy(C₁₋₄)alkyl (especially optionally substitutedpyridinyloxy- or pyrimidinyloxy(C₁₋₄)alkyl), acyloxy, including C₁₋₄alkanoyloxy (especially acetyloxy) and benzoyloxy, cyano, thiocyanato,nitro, --NR'R", --NHCOR", --NHCONR'R", --CONR'R", --COOR', --OSO₂ R',--SO₂ R' , --COR', --CR'═NR" or --N═CR'R" in which R' and R" areindependently hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl(C₁₋₄)alkyl, phenyl or benzyl, the phenyl andbenzyl groups being optionally substituted with halogen, C₁₋₄ alkyl orC₁₋₄ alkoxy.

Substituents which may be present in the aryl or heteroaryl rings of anyof the foregoing substituents and in the phenyl ring of R⁵ include oneor more of the following; halo, hydroxy, mercapto, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₂₋₄ alkenyloxy, C₂₋₄ alkynyloxy,halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, C₁₋₄ - alkylthio, hydroxy(C₁₋₄)alkyl,C₁₋₄ alkoxy(C₁₋₄)alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl(C₁₋₄)alkyl,alkanoyloxy, benzyloxy, cyano, thiocyanato, nitro, --NR'R", --NHCOR',--NHCONR'R", --CONR'R", --COOR', --OSO₂ R', --SO₂ R', --COR', --CR'═NR"or --N═CR'R" in which R' and R" have the meanings given above.

When any of the substituents A, B and E are C₁₋₄ -alkyl or C₁₋₄ alkoxy,the alkyl moiety can be in the form of straight or branched chains, thatis, the moiety may be methyl, ethyl, n- or iso-propyl, or n-, sec-, iso-or t- butyl. Other references herein to C₁₋₄ alkyl and C₁₋₄ alkoxy carrythe same meaning. C₂₋₄ Alkenyl groups can be in the form of straight orbranched chains and, where appropriate, may have either the (E)- or(Z)-configuration. Examples of such groups are vinyl, allyl,--C(CH₃):CH₂, and (E)- and (Z)-crotyl.

The substituents A and B are preferably in the 4- and 5-positions of thephenyl ring, and the substituent E is preferably a small group or asingle atom such as hydrogen or halogen. Usually, E and one or both of Aand B will be hydrogen.

In one aspect, the invention includes a compound having the formula(Ia): ##STR5## wherein X is O, S(O)_(n) in which n is 0, 1 or 2, NH,NCH₃, NCH₂ CH₃, NCOCH₃, NCH(CH₃)₂, CH₂, CH(CH₃), C(CH₃)₂, CO, C═CH₂,C═(CH₃)₂, CH₂ CH₂, CH(CH₃)CH₂, CH₂ CH(CH₃), (E)--CH═CH, (Z)--CH═CH,(E)--C(CH₃)═C(CH₃), C═C, OCH₂, OCH(CH₃), (CH₂)_(p) O in which p is aninteger of 1 to 5, CH(CH₃)O, SCH₂, SCH(CH₃), S(O)CH₂, S(O)CH(CH₃), S(O)₂CH₂, S(O)₂ CH(CH₃), CH₂ S, CH(CH₃)S, CH₂ S(O), CH(CH₃)S(O), CH₂ S(O)₂,CH(CH₃)S(O)₂, NHCH₂, N(CH₃)CH₂, N(COCH₃)CH₂, NHCH(CH₃), N(CH₃)CH(CH₃),N(COCH₃)CH(CH₃), CH₂ NH, CH₂ N(CH₃), CH₂ N(COCH₃ ), CH(CH₃)NH,CH(CH₃)N(CH₃), CH(CH₃)N(COCH₃), CO₂, O₂ C, SO₂ O, OSO₂, CO.CO, COCH₂,COCH(CH₃), CH₂ CO, CH(CH₃)CO, CH(OH)CH₂, CH(OH)CH(CH₃), CH₂ CH(OH),CH(CH₃)CH(OH), CONH, CON(CH₃), CON(CH₂ CH₂ CH₃), CON(CHO), CON(COCH₃),NHCO, N(CH₃)CO, N(CH₂ CH₃)CO, N(CHO)CO, N(COCH₃)CO, CSN(CH₃), CSNH,NHCS, N(CH₃)CS, SO₂ NH, SO₂ N(CH₃), NHSO₂, N(CH₃)SO₂, N(CH₂ CH₃)SO₂,CS₂, S₂ C, COS, SCO, (E)--N═N, (E)--N═CH, (E)--N═C(CH₃), (E)--CH₂ ═N,(E)--C(CH₃)═N, CH₂ CH₂ CH₂, CH(CH₃)CH₂ CH₂, CH₂ CH(CH₃)CH₂, CH₂ CH₂CH(CH₃), OCH₂ CH₂, CH₂ OCH₂, SCH₂ CH₂, S(O)CH₂ CH₂, S(O)₂ CH₂ CH₂, CH₂SCH₂, CH.sub. 2 S(O)CH₂, CH₂ S(O)₂ CH₂, CH₂ CH₂ S, CH₂ CH₂ S(O), CH₂ CH₂S(O)₂, (E)--CH═NNH, (E)--C(CH₂)═NNH, (E)--CH═NN(CH₃), (E)--NHN═CH,(E)--NHN═C(CH₃), (E)--N(CH₃)N═CH, CH₂ CONH, CH(CH₃)CON(CH₃),(E)--CH═CHCH₂ O, COCH₂ CH₂ O, ##STR6## CH(C₆ H₅), COCH₂ O, CH(OH), CO₂CH₂, (C₆ H₅)₂ P^(+CH) ₂ Br⁻, CH₂ OCO, CH₂ NHCO, CH₂ SCO, OCH₂ O, OCH₂CH₂ O, S(O)CH₂ O, COCH(CH₃)O, (E)--CH₂ ON═CH, (Z)--CH₂ ON═CH, CH₂ CH₂CH(OH), (E)--CH₂ CH═CH, C(CH₃)(OH), CH₂ OSO₂, CH₂ NHCO.NH, OCO.NH,NHCO.NH or CH₂ OCO.NH, A is H, hydroxy, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy,trifluoromethyl, nitro, cyano, acetyl or phenoxy; B and E are H or halo;D is H, hydroxy, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro, cyano,halo(C₁₋₄)alkyl (especially trifluoromethyl), halo(C₁₋₄)alkoxy(especially trifluoro-methoxy), phenyl, phenoxy, NHCOR⁶, NHSO₂ R⁶, NR⁷R⁸, CO₂ R⁷, wherein R⁶ is C₁₋₄ alkyl (especially methyl) or phenyl andR⁷ and R⁸ are independently H or C₁₋₄ alkyl, or CH.sub. 3 O₂ C.C═CH.OCH₃; and G is H, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy or nitro; or D and G, whenthey are adjacent, join to form a benzene or pyridine ring.

More particularly, it includes a compound having the formula (Ia)wherein X is O, OCH₂, CH₂ O, CH(OH) or SO₂ O; A is H, hydroxy, halo,C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, nitro, cyano, acetyl orphenoxy; B and E are H or halo; D is H, hydroxy, halo, C₁₋₄ alkyl, C₁₋₄alkoxy, nitro, cyano, halo(C₁₋₄)alkyl (especially trifluoromethyl),halo(C₁₋₄)alkoxy (especially trifluoromethoxy), phenyl, phenoxy, NHCOR⁶,NHSO₂ R⁶, NR⁷ R⁸ or CO₂ R⁷, wherein R⁶ is C₁₋₄ alkyl (especially methyl)or phenyl and R⁷ and R⁸ are independently H or C₁₋₄ alkyl; and G is H,halo, C₁₋₄ alkyl, C₁₋₄ alkoxy or nitro. Of special interest arecompounds of the formula (Ia) wherein X is O, OCH₂, CH₂ O or SO₂ O,; Dis H, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro, cyano or amino; and A, B, Eand G are all H.

In another aspect, the invention includes a compound having the formula(Ib): ##STR7## wherein Z is pyridinyl, pyrimidinyl, triazinyl,pyrazinyl, pyridazinyl, quinolinyl, benzoxazolyl, benzthiazolyl,thienyl, quinoxalinyl, thiazolyl, isoquinolinyl, quinazolinyl, purinyl,oxazolyl, thiadiazolyl, oxadiazolyl, furyl, pyrrolyl orthienopyrimidinyl, each optionally substituted with halo, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkylthio, halo(C₁₋₄)alkyl (especiallytrifluoromethyl), cyano, nitro, SO₂ R⁶, COOR⁷, phenyl, phenoxy, C₁₋₄alkanoyl and CONR⁷ R⁸ in which R⁶ is C₁₋₄ alkyl and R⁷ and R⁸ areindependently H or C₁₋₄ alkyl, and N-oxides thereof; X is O, S, NH,N(CH₃), SO₂ O, CH₂, CH₂ CH₂, OCH₂, CH₂ O, CH(OH), CONH or CO; A and Bare independently H, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, nitro,halo(C₁₋₄)alkyl (especially trifluoromethyl) or halo(C₁₋₄)alkoxy(especially trifluoromethoxy); and E is H or halo.

More particularly, it includes a compound having the formula (Ib)wherein X is O, OCH₂, CH₂ O, CH(OH) or SO₂ O; Z is pyridinyl,pyrimidinyl or thiazolyl, each optionally substituted with halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, halo(C₁₋₄)alkyl (especiallytrifluoromethyl), cyano, nitro, SO₂ R⁶, COOR⁷, phenyl, phenoxy, C₁₋₄alkanoyl and CONR⁷ R⁸ in which R⁶ is C₁₋₄ alkyl and R⁷ and R⁸ areindependently H or C₁₋₄ alkyl, and N-oxides thereof; A and B areindependently H, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, nitro,halo(C₁₋₄)alkyl (especially trifluoromethyl) or halo(C₁₋₄)alkoxy(especially trifluoromethoxy); and E is H or halo.

Of special interest are compounds of the formula (Ib) wherein X is O orOCH₂ ; Z is pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl or thiazol-2-yleach optionally substituted with halogen, cyano, nitro or SO₂ R⁶ inwhich R⁶ is C₁₋₄ alkyl; and A, B and E are all H.

In yet another aspect, the invention includes a compound having theformula (Ic): ##STR8## wherein X, A, B, D, E and G have the meaningsgiven for the compound (Ia).

In still yet another aspect, the invention includes a compound havingthe formula (Id): ##STR9## wherein Z, X, A, B and E have the meaningsgiven for the compound (Ib).

The invention is illustrated by the compounds listed in Tables I, II,III and IV which follow. Throughout Tables I, II, III and IV the methyl3-methoxypropenoate group has the (E)-configuration.

                                      TABLE I                                     __________________________________________________________________________     ##STR10##                                                                    Compound                                            Melting                   No.   X            D        G     A      B  E  Olefinic.sup.+                                                                     Point                     __________________________________________________________________________                                                        (°C.)              1     S            H        H     H      H  H                                 2     SO           H        H     H      H  H                                 3     SO.sub.2     H        H     H      H  H                                 4     NH           H        H     H      H  H                                 5     NCH.sub.3    H        H     H      H  H                                 6     NCH.sub.2 CH.sub.3                                                                         H        H     H      H  H                                 7     NCOCH.sub.3  H        H     H      H  H                                 8     NCH(CH.sub.3).sub.2                                                                        H        H     H      H  H                                 9     CH.sub.2     H        H     H      H  H                                 10    CH(CH.sub.3) H        H     H      H  H                                 11    C(CH.sub.3).sub.2                                                                          H        H     H      H  H                                 12    CO           H        H     H      H  H                                 13    C:CH.sub.2   H        H     H      H  H                                 14    C:C(CH.sub.3).sub.2                                                                        H        H     H      H  H                                 15    CH.sub.2 CH.sub.2                                                                          H        H     H      H  H                                 16    CH(CH.sub.3)CH.sub.2                                                                       H        H     H      H  H                                 17    CH.sub.2 CH(CH.sub.3)                                                                      H        H     H      H  H                                 18    ( .sub.-- E)CH:CH                                                                          H        H     H      H  H                                 19    ( .sub.-- E)C(CH.sub.3):C(CH.sub.3)                                                        H        H     H      H  H                                 20    C:C          H        H     H      H  H  7.58 Gum                       21    OCH.sub.2    H        H     H      H  H                                 22    OCH(CH.sub.3)                                                                              H        H     H      H  H  7.58 119-122                   23    CH.sub.2 O   H        H     H      H  H                                 24    CH(CH.sub.3)O                                                                              H        H     H      H  H                                 25    SCH.sub.2    H        H     H      H  H                                 26    SCH(CH.sub.3)                                                                              H        H     H      H  H                                 27    S(O)CH.sub.2 H        H     H      H  H                                 28    S(O)CH(CH.sub.3)                                                                           H        H     H      H  H                                 29    S(O).sub.2 CH.sub.2                                                                        H        H     H      H  H                                 30    S(O).sub.2 CH(CH.sub.3)                                                                    H        H     H      H  H                                 31    CH.sub.2 S   H        H     H      H  H                                 32    CH(CH.sub.3)S                                                                              H        H     H      H  H                                 33    CH.sub.2 S(O)                                                                              H        H     H      H  H                                 34    CH(CH.sub.3)S(O)                                                                           H        H     H      H  H                                 35    CH.sub.2 S(O).sub.2                                                                        H        H     H      H  H                                 36    CH(CH.sub.3)S(O).sub.2                                                                     H        H     H      H  H                                 37    NHCH.sub.2   H        H     H      H  H                                 38    N(CH.sub.3)CH.sub.2                                                                        H        H     H      H  H                                 39    N(COCH.sub.3)CH.sub.2                                                                      H        H     H      H  H                                 40    NHCH(CH.sub.3)                                                                             H        H     H      H  H                                 41    N(CH.sub.3)CH(CH.sub.3)                                                                    H        H     H      H  H                                 42    N(COCH.sub.3)CH(CH.sub.3)                                                                  H        H     H      H  H                                 43    CH.sub.2 NH  H        H     H      H  H                                 44    CH.sub.2 N(CH.sub.3)                                                                       H        H     H      H  H                                 45    CH.sub.2 N(COCH.sub.3)                                                                     H        H     H      H  H                                 46    CH(CH.sub.3)NH                                                                             H        H     H      H  H                                 47    CH(CH.sub.3)N(CH.sub.3)                                                                    H        H     H      H  H                                 48    CH(CH.sub.3)N(COCH.sub.3)                                                                  H        H     H      H  H                                 49    CO.sub.2     H        H     H      H  H                                 50    O.sub.2 C    H        H     H      H  H                                 51    SO.sub.2 O   H        H     H      H  H                                 52    OSO.sub.2    H        H     H      H  H                                 53    CO.CO        H        H     H      H  H                                 54    COCH.sub.2   H        H     H      H  H                                 55    COCH(CH.sub.3)                                                                             H        H     H      H  H                                 56    CH.sub.2 CO  H        H     H      H  H                                 57    CH(CH.sub.3)CO                                                                             H        H     H      H  H                                 58    CH(OH)CH.sub.2                                                                             H        H     H      H  H                                 59    CH(OH)CH(CH.sub.3)                                                                         H        H     H      H  H                                 60    CH.sub.2 CH(OH)                                                                            H        H     H      H  H                                 61    CH(CH.sub.3)CH(OH)                                                                         H        H     H      H  H                                 62    CONH         H        H     H      H  H                                 63    CON(CH.sub.3)                                                                              H        H     H      H  H                                 64    CON(CH.sub.2 CH.sub.2 CH.sub.3)                                                            H        H     H      H  H                                 65    CON(CHO)     H        H     H      H  H                                 66    CON(COCH.sub.3)                                                                            H        H     H      H  H                                 67    NHCO         H        H     H      H  H                                 68    N(CH.sub.3)CO                                                                              H        H     H      H  H                                 69    N(CH.sub.2 CH.sub.3)CO                                                                     H        H     H      H  H                                 70    N(CHO)CO     H        H     H      H  H                                 71    N(COCH.sub.3)CO                                                                            H        H     H      H  H                                 72    CSN(CH.sub.3)                                                                              H        H     H      H  H                                 73    CSNH         H        H     H      H  H                                 74    NHCS         H        H     H      H  H                                 75    N(CH.sub.3)CS                                                                              H        H     H      H  H                                 76    SO.sub.2 NH  H        H     H      H  H                                 77    SO.sub.2 N(CH.sub.3)                                                                       H        H     H      H  H                                 78    NHSO.sub.2   H        H     H      H  H                                 79    N(CH.sub.3)SO.sub. 2                                                                       H        H     H      H  H                                 80    N(CH.sub.2 CH.sub.3)SO.sub.2                                                               H        H     H      H  H                                 81    CS.sub.2     H        H     H      H  H                                 82    S.sub.2 C    H        H     H      H  H                                 83    COS          H        H     H      H  H                                 84    SCO          H        H     H      H  H                                 85    ( .sub.-- E)N:N                                                                            H        H     H      H  H                                 86    ( .sub.-- E)N:CH                                                                           H        H     H      H  H                                 87    ( .sub.-- E)N:C(CH.sub.3)                                                                  H        H     H      H  H                                 88    ( .sub.-- E)CH:N                                                                           H        H     H      H  H                                 89    ( .sub.-- E)C(CH.sub.3):N                                                                  H        H     H      H  H                                 90    CH.sub.2 CH.sub.2 CH.sub.2                                                                 H        H     H      H  H                                 91    CH(CH.sub.3)CH.sub.2 CH.sub.2                                                              H        H     H      H  H                                 92    CH.sub.2 CH(CH.sub.3)CH.sub.2                                                              H        H     H      H  H                                 93    CH.sub.2 CH.sub.2 CH(CH.sub.3)                                                             H        H     H      H  H                                 94    OCH.sub.2 CH.sub.2                                                                         H        H     H      H  H                                 95    CH.sub.2 OCH.sub.2                                                                         H        H     H      H  H                                 96    CH.sub.2 CH.sub.2 O                                                                        H        H     H      H  H                                 97    SCH.sub.2 CH.sub.2                                                                         H        H     H      H  H                                 98    S(O)CH.sub.2 CH.sub.2                                                                      H        H     H      H  H                                 99    S(O).sub.2 CH.sub.2 CH.sub.2                                                               H        H     H      H  H                                 100   CH.sub.2 SCH.sub.2                                                                         H        H     H      H  H                                 101   CH.sub.2 S(O)CH.sub.2                                                                      H        H     H      H  H                                 102   CH.sub.2 S(O).sub.2 CH.sub.2                                                               H        H     H      H  H                                 103   CH.sub.2 CH.sub.2 S                                                                        H        H     H      H  H                                 104   CH.sub.2 CH.sub.2 S(O)                                                                     H        H     H      H  H                                 105   CH.sub.2 CH.sub.2 S(O).sub.2                                                               H        H     H      H  H                                 106   ( .sub.-- E)CH:NNH                                                                         H        H     H      H  H                                 107   ( .sub.-- E)C(CH.sub.3):NNH                                                                H        H     H      H  H                                 108   ( .sub.-- E)CH:NN(CH.sub.3)                                                                H        H     H      H  H                                 109   ( .sub.-- E)NHN:CH                                                                         H        H     H      H  H                                 110   ( .sub.-- E)NHN:C(CH.sub.3)                                                                H        H     H      H  H                                 111   ( .sub.-- E)N(CH.sub.3)N:CH                                                                H        H     H      H  H                                 112   CH.sub.2 CONH                                                                              H        H     H      H  H                                 113   CH(CH.sub.3)CON(CH.sub.3)                                                                  H        H     H      H  H                                 114   CH(CH.sub.3)CON(CH.sub.3)                                                                  H        H     H      H  H                                 115   ( .sub.-- E)CH:CHCH.sub.2 O                                                                H        H     H      H  H                                 116   COCH.sub.2 CH.sub.2 O                                                                      H        H     H      H  H                                 117                                                                                  ##STR11##   H        H     H      H  H                                 118                                                                                  ##STR12##   H        H     H      H  H                                 119   O            2-Cl     H     H      H  H  7.57 88-9                      120   O            3-Cl     H     H      H  H                                 121   O            4-Cl     H     H      H  H                                 122   O            2-F      H     H      H  H                                 123   O            3-F      H     H      H  H                                 124   O            4-F      H     H      H  H                                 125   O            2-CH.sub.3                                                                             H     H      H  H                                 126   O            3-CH.sub.3                                                                             H     H      H  H                                 127   O            4-CH.sub.3                                                                             H     H      H  H                                 128   O            2-CH.sub.3 O                                                                           H     H      H  H  7.57 Gum                       129   O            3-CH.sub.3 O                                                                           H     H      H  H                                 130   O            4-CH.sub.3 O                                                                           H     H      H  H                                 131   O            2-NO.sub.2                                                                             H     H      H  H  7.58 99-100                    132   O            3-NO.sub.2                                                                             H     H      H  H                                 133   O            4-NO.sub.2                                                                             H     H      H  H  7.59 102-103                   134   O            2-CN     H     H      H  H  7.58 Gum                       135   O            3-CN     H     H      H  H                                 136   O            4-CN     H     H      H  H                                 137   O            2-Br     H     H      H  H                                 138   O            3-Br     H     H      H  H                                 139   O            4-Br     H     H      H  H                                 140   O            2-CF.sub.3                                                                             H     H      H  H                                 141   O            3-CF.sub.3                                                                             H     H      H  H                                 142   O            4-CF.sub.3                                                                             H     H      H  H                                 143   O            2-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 144   O            3-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 145   O            4-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 146   O            2-CH.sub.3 CH.sub.2 O                                                                  H     H      H  H                                 147   O            3-CH.sub.3 CH.sub.2 O                                                                  H     H      H  H                                 148   O            4-CH.sub.3 CH.sub.2 O                                                                  H     H      H  H                                 149   O            2-C.sub.2 H.sub.5                                                                      H     H      H  H                                 150   O            3-C.sub.6 H.sub.5                                                                      H     H      H  H                                 151   O            4-C.sub.6 H.sub.5                                                                      H     H      H  H                                 152   O            2-Cl     3-Cl  H      H  H                                 153   O            2-Cl     4-Cl  H      H  H                                 154   O            2-Cl     5-Cl  H      H  H                                 155   O            2-Cl     6-Cl  H      H  H                                 156   O            3-Cl     4-Cl  H      H  H                                 157   O            3-Cl     5-Cl  H      H  H                                 158   O            2-Cl     3-CH.sub.3 O                                                                        H      H  H                                 159   O            2-Cl     4-CH.sub.3 O                                                                        H      H  H                                 160   O            2-Cl     5-CH.sub.3 O                                                                        H      H  H                                 161   O            2-Cl     6-CH.sub.3 O                                                                        H      H  H                                 162   O            3-Cl     4-CH.sub.3 O                                                                        H      H  H                                 163   O            3-Cl     5-CH.sub.3 O                                                                        H      H  H                                 164   O            2-CH.sub.3 O                                                                           3-Cl  H      H  H                                 165   O            2-CH.sub.3 O                                                                           4-Cl  H      H  H                                 166   O            2-CH.sub.3 O                                                                           5-Cl  H      H  H                                 167   O            3-CH.sub. 3 O                                                                          4-Cl  H      H  H                                 168   O                           H      H  H                                 169   O                           H      H  H                                 170   O            H        H     2-F    H  H                                 171   O            H        H     4-F    H  H                                 172   O            H        H     5-F    H  H                                 173   O            H        H     6-F    H  H                                 174   O            H        H     4-Cl   H  H                                 175   O            H        H     5-Cl   H  H                                 176   O            H        H     4-CH.sub.3                                                                           H  H                                 177   O            H        H     5-CH.sub.3                                                                           H  H                                 178   O            H        H     4-CH.sub.3 O                                                                         H  H                                 179   O            H        H     5-CH.sub.3 O                                                                         H  H                                 180   O            H        H     4-Br   H  H                                 181   O            H        H     5-Br   H  H                                 182   O            H        H     4-CF.sub.3                                                                           H  H                                 183   O            H        H     5-CF.sub.3                                                                           H  H                                 184   O            H        H     4-NO.sub.2                                                                           H  H                                 185   O            H        H     5-NO.sub.2                                                                           H  H                                 186   O            H        H     4-CN   H  H                                 187   O            H        H     5-CN   H  H                                 188   O            H        H     4-F    5-F                                                                              H                                 189   O            H        H     4-Cl   5-Cl                                                                             H                                 190   O            H        H     4-F    5-Cl                                                                             H                                 191   O            H        H     4-Cl   5-F                                                                              H                                 192   O            H        H     4-CH.sub.3 O                                                                         5-Cl                                                                             H                                 193   O            H        H     4-CH.sub. 3 O                                                                        5-F                                                                              H                                 194   O            H        H     H      H  5-F                               195   O            H        H     H      H  6-Cl                              196   ( .sub.-- E)N:N                                                                            H        H     4-CH.sub.3 O                                                                         H  H                                 197   ( .sub.-- E)N:N                                                                            H        H     4-CH.sub.3 CH.sub.2 O                                                                H  H                                 198   CH.sub.2 O   2-Cl     H     H      H  H                                 199   CH.sub.2 O   3-Cl     H     H      H  H                                 200   CH.sub.2 O   4-Cl     H     H      H  H                                 201   CH.sub.2 O   2-F      H     H      H  H                                 202   CH.sub.2 O   3-F      H     H      H  H                                 203   CH.sub.2 O   4-F      H     H      H  H                                 204   CH.sub.2 O   2-CH.sub.3                                                                             H     H      H  H                                 205   CH.sub.2 O   3-CH.sub.3                                                                             H     H      H  H                                 206   CH.sub.2 O   4-CH.sub.3                                                                             H     H      H  H                                 207   CH.sub.2 O   2-CH.sub.3 O                                                                           H     H      H  H                                 208   CH.sub.2 O   3-CH.sub.3 O                                                                           H     H      H  H                                 209   CH.sub.2 O   4-CH.sub.3 O                                                                           H     H      H  H                                 210   CH.sub.2 O   2-NO.sub.2                                                                             H     H      H  H                                 211   CH.sub.2 O   3-NO.sub.2                                                                             H     H      H  H                                 212   CH.sub.2 O   4-NO.sub.2                                                                             H     H      H  H  7.58 125- 127                  213   CH.sub.2 O   2-CN     H     H      H  H                                 214   CH.sub.2 O   3-CN     H     H      H  H                                 215   CH.sub.2 O   4-CN     H     H      H  H                                 216   CH.sub.2 O   2-Br     H     H      H  H                                 217   CH.sub.2 O   3-Br     H     H      H  H                                 218   CH.sub.2 O   4-Br     H     H      H  H                                 219   CH.sub.2 O   2-CF.sub.3                                                                             H     H      H  H                                 220   CH.sub.2 O   3-CF.sub.3                                                                             H     H      H  H                                 221   CH.sub.2 O   4-CF.sub.3                                                                             H     H      H  H                                 222   CH.sub.2 O   2-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 223   CH.sub.2 O   3-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 224   CH.sub.2 O   4-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 225   CH.sub.2 O   2-CH.sub.3 CH.sub.2 O                                                                  H     H      H  H                                 226   CH.sub.2 O   3-CH.sub.3 CH.sub.2 O                                                                  H     H      H  H                                 227   CH.sub.2 O   4-CH.sub.3 CH.sub.2 O                                                                  H     H      H  H                                 228   CH.sub.2 O   2-C.sub.6 H.sub.5                                                                      H     H      H  H                                 229   CH.sub.2 O   3-C.sub.6 H.sub.5                                                                      H     H      H  H                                 230   CH.sub.2 O   4-C.sub.6 H.sub.5                                                                      H     H      H  H                                 231   CH.sub.2 O   2-Cl     3-Cl  H      H  H                                 232   CH.sub.2 O   2-Cl     4-Cl  H      H  H                                 233   CH.sub.2 O   2-Cl     5-Cl  H      H  H                                 234   CH.sub.2 O   2-Cl     6-Cl  H      H  H                                 235   CH.sub.2 O   3-Cl     4-Cl  H      H  H                                 236   CH.sub.2 O   3-Cl     5-Cl  H      H  H                                 237   CH.sub.2 O   2-Cl     3-CH.sub.3 O                                                                        H      H  H                                 238   CH.sub.2 O   2-Cl     4-CH.sub.3 O                                                                        H      H  H                                 239   CH.sub.2 O   2-Cl     5-CH.sub.3 O                                                                        H      H  H                                 240   CH.sub.2 O   2-Cl     6-CH.sub.3 O                                                                        H      H  H                                 241   CH.sub.2 O   3-Cl     4-CH.sub.3 O                                                                        H      H  H                                 242   CH.sub.2 O   3-Cl     5-CH.sub.3 O                                                                        H      H  H                                 243   CH.sub.2 O   2-CH.sub.3 O                                                                           3-Cl  H      H  H                                 244   CH.sub.2 O   2-CH.sub.3 O                                                                           4-Cl  H      H  H                                 245   CH.sub.2 O   2-CH.sub.3 O                                                                           5-Cl  H      H  H                                 246   CH.sub.2 O   3-CH.sub.3 O                                                                           4-Cl  H      H  H                                 247   CH.sub.2 O                  H      H  H                                 248   CH.sub.2 O                  H      H  H                                 249   CH.sub.2 O   H        H     2-F    H  H                                 250   CH.sub.2 O   H        H     4-F    H  H                                 251   CH.sub.2 O   H        H     5-F    H  H                                 252   CH.sub.2 O   H        H     6-F    H  H                                 253   CH.sub.2 O   H        H     4-Cl   H  H                                 254   CH.sub.2 O   H        H     5-Cl   H  H                                 255   CH.sub.2 O   H        H     4-CH.sub.3                                                                           H  H                                 256   CH.sub.2 O   H        H     5-CH.sub.3                                                                           H  H                                 257   CH.sub.2 O   H        H     4-CH.sub.3 O                                                                         H  H                                 258   CH.sub.2 O   H        H     5-CH.sub.3 O                                                                         H  H                                 259   CH.sub.2 O   H        H     4-Br   H  H                                 260   CH.sub.2 O   H        H     5-Br   H  H                                 261   CH.sub.2 O   H        H     4-CF.sub.3                                                                           H  H                                 262   CH.sub.2 O   H        H     5-CF.sub.3                                                                           H  H                                 263   CH.sub.2 O   H        H     4-NO.sub.2                                                                           H  H                                 264   CH.sub.2 O   H        H     5-NO.sub.2                                                                           H  H                                 265   CH.sub.2 O   H        H     4-CN   H  H                                 266   CH.sub.2 O   H        H     5-CN   H  H                                 267   CH.sub.2 O   H        H     4-F    5-F                                                                              H                                 268   CH.sub.2 O   H        H     4-Cl   5-Cl                                                                             H                                 269   CH.sub.2 O   H        H     4-F    5-Cl                                                                             H                                 270   CH.sub.2 O   H        H     4-Cl   5-F                                                                              H                                 271   CH.sub.2 O   H        H     4-CH.sub.3 O                                                                         5-Cl                                                                             H                                 272   CH.sub.2 O   H        H     4-CH.sub.3 O                                                                         5-F                                                                              H                                 273   CH.sub.2 O   H        H     H      H  5-F                               274   CH.sub.2 O   H        H     H      H  6-Cl                              275   O            4-NH.COCH.sub.3                                                                        H     H      H  H                                 276   O            4-NH.SO.sub.2 C.sub.6 H.sub.5                                                          H     H      H  H                                 277   O            4-NH.COC.sub.6 H.sub.5                                                                 H     H      H  H                                 278   O            4-NH.SO.sub.2 CH.sub.3                                                                 H     H      H  H                                 279   O            4-N(CH.sub.3).sub.2                                                                    H     H      H  H                                 280   SO.sub.2 O   4-NH.COCH.sub.3                                                                        H     H      H  H                                 281   SO.sub.2 O   3-NO.sub.2                                                                             4-Cl  H      H  H                                 282   ( .sub.-- E)N:N                                                                            4-Cl     H     4-HO   H  H                                 283   SO.sub.2 O   2-Cl     H     H      H  H                                 284   SO.sub.2 O   3-Cl     H     H      H  H                                 285   SO.sub.2 O   4-Cl     H     H      H  H                                 286   SO.sub.2 O   2-F      H     H      H  H                                 287   SO.sub.2 O   3-F      H     H      H  H                                 288   SO.sub.2 O   4-F      H     H      H  H                                 289   SO.sub.2 O   2-CH.sub.3                                                                             H     H      H  H                                 290   SO.sub.2 O   3-CH.sub.3                                                                             H     H      H  H                                 291   SO.sub.2 O   4-CH.sub.3                                                                             H     H      H  H                                 292   SO.sub.2 O   2-CH.sub.3 O                                                                           H     H      H  H                                 293   SO.sub.2 O   3-CH.sub.3 O                                                                           H     H      H  H                                 294   SO.sub.2 O   4-CH.sub.3 O                                                                           H     H      H  H                                 295   SO.sub.2 O   2-NO.sub.2                                                                             H     H      H  H                                 296   SO.sub.2 O   3-NO.sub.2                                                                             H     H      H  H  7.57 49-51                     297   SO.sub.2 O   4-NO.sub.2                                                                             H     H      H  H                                 298   SO.sub.2 O   2-CN     H     H      H  H                                 299   SO.sub.2 O   3-CN     H     H      H  H                                 300   SO.sub.2 O   4-CN     H     H      H  H                                 301   SO.sub.2 O   2-Br     H     H      H  H                                 302   SO.sub.2 O   3-Br     H     H      H  H                                 303   SO.sub.2 O   4-Br     H     H      H  H                                 304   SO.sub.2 O   2-CF.sub.3                                                                             H     H      H  H                                 305   SO.sub.2 O   3-CF.sub.3                                                                             H     H      H  H                                 306   SO.sub.2 O   4-CF.sub.3                                                                             H     H      H  H                                 307   SO.sub.2 O   2-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 308   SO.sub.2 O   3-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 309   SO.sub.2 O   4-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 310   SO.sub.2 O   2-CH.sub.3 CH.sub.2 O                                                                  H     H      H  H                                 311   SO.sub. 2 O  3-CH.sub.3 CH.sub.2 O                                                                  H     H      H  H                                 312   SO.sub.2 O   4-CH.sub.3 CH.sub.2 O                                                                  H     H      H  H                                 313   SO.sub.2 O   2-C.sub.6 H.sub.5                                                                      H     H      H  H                                 314   SO.sub.2 O   3-C.sub.6 H.sub.5                                                                      H     H      H  H                                 315   SO.sub.2 O   4-C.sub.6 H.sub.5                                                                      H     H      H  H                                 316   SO.sub.2 O   2-Cl     3-Cl  H      H  H                                 317   SO.sub.2 O   2-Cl     4-Cl  H      H  H                                 318   SO.sub.2 O   2-Cl     5-Cl  H      H  H                                 319   SO.sub.2 O   2-Cl     6-Cl  H      H  H                                 320   SO.sub.2 O   3-Cl     4-Cl  H      H  H                                 321   SO.sub.2 O   3-Cl     5-Cl  H      H  H                                 322   SO.sub.2 O   2-Cl     3-CH.sub.3 O                                                                        H      H  H                                 323   SO.sub.2 O   2-Cl     4-CH.sub.3 O                                                                        H      H  H                                 324   SO.sub.2 O   2-Cl     5-CH.sub.3 O                                                                        H      H  H                                 325   SO.sub.2 O   2-Cl     6-CH.sub.3 O                                                                        H      H  H                                 326   SO.sub.2 O   3-Cl     4-CH.sub.3 O                                                                        H      H  H                                 327   SO.sub.2 O   3-Cl     5-CH.sub.3 O                                                                        H      H  H                                 328   SO.sub.2 O   2-CH.sub.3 O                                                                           3-Cl  H      H  H                                 329   SO.sub.2 O   2-CH.sub.3 O                                                                           4-Cl  H      H  H                                 330   SO.sub.2 O   2-CH.sub.3 O                                                                           5-Cl  H      H  H                                 331   SO.sub.2 O   3-CH.sub.3 O                                                                           4-Cl  H      H  H                                 332   SO.sub.2 O                  H      H  H                                 333   SO.sub.2 O                  H      H  H                                 334   SO.sub.2 O   H        H     2-F    H  H                                 335   SO.sub.2 O   H        H     4-F    H  H                                 336   SO.sub.2 O   H        H     5-F    H  H                                 337   SO.sub.2 O   H        H     6-F    H  H                                 338   SO.sub.2 O   H        H     4-Cl   H  H                                 339   SO.sub.2 O   H        H     5-Cl   H  H                                 340   SO.sub.2 O   H        H     4-CH.sub.3                                                                           H  H                                 341   SO.sub.2 O   H        H     5-CH.sub.3                                                                           H  H                                 342   SO.sub.2 O   H        H     4-CH.sub.3                                                                           H  H                                 343   SO.sub.2 O   H        H     5-CH.sub.3                                                                           H  H                                 344   SO.sub.2 O   H        H     4-Br   H  H                                 345   SO.sub.2 O   H        H     5-Br   H  H                                 346   SO.sub.2 O   H        H     4-CF.sub.3                                                                           H  H                                 347   SO.sub.2 O   H        H     5-CF.sub.3                                                                           H  H                                 348   SO.sub.2 O   H        H     4-NO.sub.2                                                                           H  H                                 349   SO.sub.2 O   H        H     5-NO.sub.2                                                                           H  H                                 350   SO.sub. 2 O  H        H     4-CN   H  H                                 351   SO.sub.2 O   H        H     5-CN   H  H                                 352   SO.sub.2 O   H        H     4-F    5-F                                                                              H                                 353   SO.sub.2 O   H        H     4-Cl   5-Cl                                                                             H                                 354   SO.sub.2 O   H        H     4-F    5-Cl                                                                             H                                 355   SO.sub.2 O   H        H     4-Cl   5-F                                                                              H                                 356   SO.sub.2 O   H        H     4-CH.sub.3 O                                                                         5-Cl                                                                             H                                 357   SO.sub.2 O   H        H     3-CH.sub.3 O                                                                         5-F                                                                              H                                 358   SO.sub.2 O   H        H     H      H  5-F                               359   SO.sub.2 O   H        H     H      H  6-Cl                              360   CH(C.sub.6 H.sub.5)                                                                        H        H     H      H  H                                 361   O            3-Cl     H     4-Cl   H  H                                 362   O            3-CH.sub.3 O                                                                           4-Cl  5-F    H  H                                 363   CH.sub.2 O   4-F      H     5-CH.sub.3 O                                                                         H  H                                 364   SO.sub.2 O   3-CH.sub.3                                                                             H     4-F    H  H                                 365+  O            H        H     4-CH.sub.3 CO                                                                        H  H                                 366+  O            H        H     6-CH.sub.3 CO                                                                        H  H                                 367*  O            H        H     6-Br   H  H                                 368   O            H        H     5-C.sub.6 H.sub.5 O                                                                  H  H                                 369   SO.sub.2 O   3-NH.sub.2                                                                             H     H      H  H                                 370   COCH.sub.2 O H        H     H      H  H                                 371   OCH.sub.2    4-CH.sub. 3 O                                                                          H     H      H  H                                 372   OCH.sub.2    3-CH.sub.3 O                                                                           H     H      H  H                                 373   OCH.sub.2    3-CN     H     H      H  H                                 374   OCH.sub.2    4-CN     H     H      H  H                                 375   OCH.sub.2    4-NO.sub.2                                                                             H     H      H  H                                 376   OCH.sub.2    2-Cl     H     H      H  H  7.58 120-122                   377   OCH.sub.2    2-CH.sub.3 O                                                                           H     H      H  H                                 378   OCH.sub.2    2-CN     H     H      H  H                                 379   ( .sub.-- E)N:N                                                                            4-Cl     H     4-CH.sub.3 O                                                                         H  H                                 380   CH(OH)       H        H     H      H  H  7.55 Oil                       381   OCH.sub.2    2-NO.sub.2                                                                             H     H      H  H  7.58 142-143                   382   OCH.sub.2    3-NO.sub.2                                                                             H     H      H  H                                 383   OCH.sub.2    3-Br     H     H      H  H                                 384   OCH.sub.2    3-Cl     H     H      H  H                                 385   OCH.sub.2    3-C.sub.6 H.sub.5 O                                                                    H     H      H  H                                 386   OCH.sub.2    4-Cl     H     H      H  H                                 387   S(O)CH.sub.2 4-Cl     H     H      H  H                                 388   S(O).sub.2 CH.sub.2                                                                        4-Cl     H     H      H  H                                 389   OCH.sub.2    2-Br     H     H      H  H                                 390   O            2-NO.sub.2                                                                             4-NO.sub.2                                                                          H      H  H                                 391   O            2-Me     3-Me  H      H  H                                 392   O            2-Me     4-Me  H      H  H                                 393   O            2-Me     5-Me  H      H  H                                 394   O            2-Me     6-Me  H      H  H                                 395   O            3-Me     4-Me  H      H  H                                 396   O            3-Me     5-Me  H      H  H                                 397   OCH.sub.2    4-Br     H     H      H  H                                 398   CO.sub.2 CH.sub.2                                                                          H        H     H      H  H                                 399   SCH.sub.2    2-Cl     H     H      H  H                                 400   SCH.sub.2    4-NO.sub.2                                                                             H     H      H  H                                 401   S(O)CH.sub.2 2-Cl     H     H      H  H                                 402   S(O).sub.2 CH.sub.2                                                                        2-Cl     H     H      H  H                                 403   ( .sub.-- E/ .sub.-- Z)CHCH                                                                4-NO.sub.2                                                                             H     H      H  H                                 404   Ph.sub.2.sup.+ PCH.sub.2 Br.sup.-                                                          H        H     H      H  H                                 405   CH.sub.2 O   4- .sub.- t-C.sub.4 H.sub.9                                                            H     H      H  H                                 406   CH.sub.2 OCO H        H     H      H  H                                 407   CH.sub.2 NHCO                                                                              H        H     H      H  H                                 408   CH.sub.2 SCO H        H     H      H  H                                 409   O.sub.2 C    3-NO.sub.2                                                                             H     H      H  H                                 410   OCH.sub.2 O  4-Cl     H     H      H  H                                 411   S(O)CH.sub.2 O                                                                             H        H     H      H  H                                 412   COCH(CH.sub.3)O                                                                            H        H     H      H  H                                 413   ( .sub.-- E)CH.sub.2 ON:CH                                                                 H        H     H      H  H                                 414   ( .sub.-- Z)CH.sub.2 ON:CH                                                                 H        H     H      H  H                                 415   (CH.sub.2).sub.3 O                                                                         H        H     H      H  H                                 416   (CH.sub.2).sub.4 O                                                                         H        H     H      H  H                                 417   (CH.sub.2).sub.5 O                                                                         H        H     H      H  H                                 418   ( .sub.-- E)N:N                                                                            4-OH     H     H      H  H                                 419   ( .sub.-- E)N:N                                                                            4-CH.sub.3 O                                                                           H     H      H  H                                 420   CO.NH        2-Br     H     H      H  H                                 421   CO.NH        3-Br     H     H      H  H                                 422   CO.NH        3-CH.sub.3 O                                                                           H     H      H  H                                 423   OCH.sub.2 CH.sub.2 O                                                                       H        H     H      H  H                                 424   SO.sub.2 O                  H      H  H                                 425   SCH.sub.2 O  H        H     H      H  H                                 426   CH.sub.2 O   2-(CH.sub.3 O.sub.2 C                                                                  H     H      H  H                                                    CCH.OCH.sub.3)                                             427   SO.sub.2 O   4-CF.sub.3 O                                                                           H     H      H  H                                 428   SO.sub.2 O   2-CH.sub.3 O.sub.2 C                                                                   H     H      H  H                                 429   CH.sub.2 CH.sub.2 CH(OH)                                                                   H        H     H      H  H                                 430   ( .sub.-- E)CH.sub.2 CHCH                                                                  H        H     H      H  H                                 431   C(CH.sub.3)(OH)                                                                            H        H     H      H  H                                 432   CH(OH)       2-Cl     H     H      H  H                                 433   CH(OH)       4-Cl     H     H      H  H                                 434   CH(OH)       2-CH.sub.3 O                                                                           H     H      H  H                                 435   CH(OH)       3-CF.sub.3                                                                             H     H      H  H                                 436   CH(OH)       3-CN     H     H      H  H                                 437   CH(OH)       4-NO.sub.2                                                                             H     H      H  H                                 438   CH.sub.2 OSO.sub.2                                                                         H        H     H      H  H                                 439   CH.sub.2 NHCO.NH                                                                           H        H     H      H  H                                 440   CH.sub.2 NH  H        H     H      H  H                                 441   OCO.NH       H        H     H      H  H                                 442   NHCO.NH      H        H     H      H  H                                 443   CH.sub.2 OCO.NH                                                                            H        H     H      H  H                                 444   SO.sub.2 NH  4-Br     H     H      H  H                                 445   CH.sub.2 NH  3-CH.sub.3                                                                             H     H      H  H                                 446   O            H        H     H      H  H  7.56 79-81                     447   O            2-NH.sub.2                                                                             H     H      H  H  7.57 Oil                       __________________________________________________________________________    TABLE I - FOOTNOTES:                                                          +Chemical shift of singlet from olefinic proton on beta-methoxypropenoate     group (p.p.m from tetramethylsilane).                                         Solvent: CDCl.sub.3 unless otherwise stated.                                   Substituents D and G join to form a fused ring. Thus compound numbers        168, 169, 247, 248, 332 and 333 are:                                           ##STR13##                                                                    X   COMPOUND                                                                  O   168                                                                       CH.sub.2 O                                                                        247                                                                       SO.sub.2 O                                                                        332                                                                        ##STR14##                                                                    X   COMPOUND                                                                  O   169                                                                       CH.sub.2 O                                                                        248                                                                       SO.sub.2 O                                                                        333                                                                       And Compound No. 424 is:                                                       ##STR15##                                                                

    TABLE II                                                                      __________________________________________________________________________     ##STR16##                                                                    Compound                                    Melting                           No.   Z            X    A    B    E    Olefinic.sup.+                                                                     Point (°C.)                __________________________________________________________________________     1    Pyridin-2-yl O    H    H    H                                            2    Pyridin-2-yl S    H    H    H                                            3    Pyridin-2-yl N(CH.sub.3)                                                                        H    H    H                                            4    Pyridin-2-yl SO.sub.2 O                                                                         H    H    H                                            5    Pyridin-2-yl CH.sub.2 CH.sub.2                                                                  H    H    H                                            6    Pyridin-2-yl OCH.sub.2                                                                          H    H    H    7.58 Oil                                7    Pyridin-2-yl CH.sub.2 O                                                                         H    H    H                                            8    Pyridin-3-yl O    H    H    H                                            9    Pyridin-3-yl S    H    H    H                                            10   Pyridin-3-yl N(CH.sub.3)                                                                        H    H    H                                             11  Pyridin-3-yl SO.sub.2 O                                                                         H    H    H                                            12   Pyridin-3-yl CH.sub.2 CH.sub.2                                                                  H    H    H                                            13   Pyridin-3-yl OCH.sub.2                                                                          H    H    H                                            14   Pyridin-3-yl CH.sub.2 O                                                                         H    H    H                                            15   Pyridin-4-yl O    H    H    H                                            16   Pyridin-4-yl S    H    H    H                                            17   Pyridin-4-yl N(CH.sub.3)                                                                        H    H    H                                            18   Pyridin-4-yl SO.sub.2 O                                                                         H    H    H                                            19   Pyridin-4-yl CH.sub.2 CH.sub.2                                                                  H    H    H                                            20   Pyridin-4-yl OCH.sub.2                                                                          H    H    H                                            21   Pyridin-4-yl CH.sub.2 O                                                                         H    H    H                                            22   Pyrimidin-2-yl                                                                             O    H    H    H    7.57 151-153                            23   Pyrimidin-2-yl                                                                             S    H    H    H                                            24   Pyrimidin-4-yl                                                                             N(CH.sub.3)                                                                        H    H    H                                            25   Pyrimidin-4-yl                                                                             SO.sub.2 O                                                                         H    H    H                                            26   Pyrimidin-5-yl                                                                             CH.sub.2 CH.sub.2                                                                  H    H    H                                            27   Pyrimidin-5-yl                                                                             CH.sub.2 O                                                                         H    H    H                                            28   1,2,4-Triazin-3-yl                                                                         OCH.sub.2                                                                          H    H    H                                            29   1,3,5-Triazin-2-yl                                                                         O    H    H    H                                            30   Pyrazin-2-yl O    H    H    H                                            31   Pyrazin-2-yl S    H    H    H                                            32   Pyrazin-2-yl N(CH.sub.3)                                                                        H    H    H                                            33   Pyrazin-2-yl SO.sub.2 O                                                                         H    H    H                                            34   Pyrazin-2-yl CH.sub.2 O                                                                         H    H    H                                            35   Pyridazin-3-yl                                                                             O    H    H    H                                            36   Pyridazin-3-yl                                                                             S    H    H    H                                            37   Pyridazin-3-yl                                                                             SO.sub.2 O                                                                         H    H    H                                            38   Quinolin-2-yl                                                                              O    H    H    H                                            39   Quinolin-2-yl                                                                              CH.sub.2 O                                                                         H    H    H                                            40   Quinolin-3-yl                                                                              O    H    H    H                                            41   Quinolin-3-yl                                                                              SO.sub.2 O                                                                         H    H    H                                            42   Benzoxazol-2-yl                                                                            O    H    H    H                                            43   Benzoxazol-2-yl                                                                            S    H    H    H                                            44   Benzoxazol-2-yl                                                                            N(CH.sub.3)                                                                        H    H    H                                            45   Benzoxazol-2-yl                                                                            SO.sub.2 O                                                                         H    H    H                                            46   Benzthiazol-2-yl                                                                           CH.sub.2 CH.sub.2                                                                  H    H    H                                            47   Benzthiazol-2-yl                                                                           OCH.sub.2                                                                          H    H    H                                            48   Benzthiazol-2-yl                                                                           CH.sub.2 O                                                                         H    H    H                                            49   Thien-2-yl   CH.sub.2 O                                                                         H    H    H                                            50   Thien-2-yl   CH.sub.2 CH.sub.2                                                                  H    H    H                                            51   Thien-3-yl   O    H    H    H                                            52   Thien-2-yl   SO.sub.2 O                                                                         H    H    H                                            53   5-CF.sub.3 -Pyridin-2-yl                                                                   O    H    H    H                                            54   5-CF.sub.3 -Pyridin-2-yl                                                                   S    H    H    H                                            55   5-CF.sub.3 -Pyridin-2-yl                                                                   CH.sub.2 O                                                                         H    H    H                                            56   3-F-Pyridin-2-yl                                                                           O    H    H    H                                            57   3-Cl-Pyridin-2-yl                                                                          O    H    H    H                                            58   4-Br-Pyridin-2-yl                                                                          O    H    H    H                                            59   5-CH.sub.3 -Pyridin-2-yl                                                                   O    H    H    H                                            60   6-CH.sub.3 O-Pyridin-2-yl                                                                  O    H    H    H                                            61   2-F-Pyridin-3-yl                                                                           O    H    H    H                                            62   3-CF.sub.3 -Pyridin-4-yl                                                                   O    H    H    H                                            63   4,6-di-F-Pyridin-2-yl                                                                      O    H    H    H                                            64   3-NO.sub.2 -5-CF.sub.3 -                                                                   O    H    H    H                                                 Pyridin-2-yl                                                             65   5-(CH.sub.3 O.sub.2 C)-                                                                    O    H    H    H                                                 Pyridin-2-yl                                                             66   3-CH.sub.3 -Pyridin-2-yl                                                                   O    H    H    H                                            67   4-CH.sub.3 -Pyridin-2-yl                                                                   O    H    H    H                                            68   6-CH.sub.3 -Pyridin-2-yl                                                                   O    H    H    H                                            69   5-(CN)-Pyridin-2-yl                                                                        O    H    H    H                                            70   3-Cl-5-(C.sub.6 H.sub.5 O)-1,                                                              O    H    H    H                                                 3,5-triazin-2-yl                                                         71   Pyridin-2-yl O    2-F  H    H                                            72   Pyridin-2-yl O    4-Cl H    H                                            73   Pyridin-4-yl O    5-CH.sub.3                                                                         H    H                                            74   Pyridin-4-yl O    4-CH.sub.3 O                                                                       H    H                                            75   5-CF.sub.3 -Pyridin-2-yl                                                                   O    5-CN H    H                                            76   5-CF.sub.3 -Pyridin-2-yl                                                                   O    4-F  5-CH.sub.3 O                                                                       H                                            77   Pyrimidin-2-yl                                                                             O    H    H    5-Cl                                         78   Pyrimidin-2-yl                                                                             O    H    H    6-F                                          79   Benzoxazol-2-yl                                                                            O    4-CF.sub.3 O                                                                       H    5-F                                          80   Benzoxazol-2-yl                                                                            O    5-NO.sub.2                                                                         H    H                                             81  1,2,4-Triazol-1-yl                                                                         CH.sub.2                                                                           H    H    H                                            82   1,2,3-Triazol-1-yl                                                                         CH.sub.2                                                                           H    H    H                                            83   Benzthiazol-2-yl                                                                           O    H    H    H                                            84   3-Chloroquinoxalin-2-yl                                                                    O    H    H    H                                            85   Pyrimidin-2-yl                                                                             OCH.sub.2                                                                          H    H    H                                            86   3,5-di-Cl-1,3,5-                                                                           O    H    H    H                                                 triazin-2-yl                                                             87   Pyrimidin-5-yl                                                                             O    H    H    H                                            88   3-Cl,5-(CH.sub.3 O)-1,3,5-                                                                 O    H    H    H                                                 triazin-2-yl                                                             89   6-Cl-Pyrimidin-4-yl                                                                        O    H    H    H    7.59 82-84                              90   5-Br-Pyrimidin-2-yl                                                                        O    H    H    H                                            91   5-Cl-Pyrimidin-2-yl                                                                        O    H    H    H                                            92   Pyrimidin-4-yl                                                                             O    H    H    H                                            93   2,6-Di-CH.sub.3 O-                                                                         O    H    H    H                                                 Pyrimidin-4-yl                                                           94   2-Cl-6-CH.sub.3 -Pyrimidin-                                                                O    H    H    H                                                 4-yl                                                                     95   2,6-Di-Cl-Pyrimidin-                                                                       O    H    H    H                                                 4-yl                                                                     96   2,5,6-Tri-Cl-                                                                              O    H    H    H                                                 Pyrimidin-4-yl                                                           97   2-Cl-Pyrimidin-4-yl                                                                        O    H    H    H    7.60 115-118                            98   2-CH.sub.3 -Thiazol-4-yl                                                                   CH.sub.2 O                                                                         H    H    H                                            99   Benzoxazol-2-yl                                                                            OCH.sub.2                                                                          H    H    H                                           100   Pyrazin-2-yl OCH.sub.2                                                                          H    H    H                                           101   6-Cl-Pyrazin-2-yl                                                                          OCH.sub.2                                                                          H    H    H                                           102   Quinolin-2-yl                                                                              OCH.sub.2                                                                          H    H    H                                           103   6-Cl-Pyridazin-3-yl                                                                        OCH.sub.2                                                                          H    H    H                                           104   Pyridin-4-yl,  .sub.-- N-oxide                                                             OCH.sub.2                                                                          H    H    H                                           105   5-CF.sub.3 -Pyridin-2-yl                                                                   OCH.sub.2                                                                          H    H    H                                           106   3-Cyanopyridin-2-yl                                                                        O    H    H    H    7.58 109-112                           107   5-NO.sub.2 -Pyridin-2-yl                                                                   O    H    H    H                                           108   Pyrimidin-2-yl                                                                             CH.sub.2 O                                                                         H    H    H                                           109   Pyrimidin-2-yl                                                                             SO.sub.2 O                                                                         H    H    H                                           110   Pyrimidin-2-yl                                                                             NH   H    H    H                                           111   Pyrimidin-2-yl                                                                             N(CH.sub.3)                                                                        H    H    H                                           112   Pyrimidin-2-yl                                                                             CH.sub.2                                                                           H    H    H                                           113   Pyrimidin-2-yl                                                                             CH(OH)                                                                             H    H    H                                           114   Pyrimidin-2-yl                                                                             CH.sub.2 CH.sub.2                                                                  H    H    H                                           115   Pyrimidin-4-yl                                                                             O    H    H    H                                           116   Pyrimidin-4-yl                                                                             CH.sub.2 O                                                                         H    H    H                                           117   Pyrimidin-4-yl                                                                             OCH.sub.2                                                                          H    H    H                                           118   Pyrimidin-4-yl                                                                             NH   H    H    H                                           119   Pyrimidin-4-yl                                                                             S    H    H    H                                           120   Pyrimidin-4-yl                                                                             CH.sub.2                                                                           H    H    H                                           121   Pyrimidin-4-yl                                                                             CH(OH)                                                                             H    H    H                                           122   Pyrimidin-4-yl                                                                             CH.sub.2 CH.sub.2                                                                  H    H    H                                           123   Pyrimidin-5-yl                                                                             SO.sub.2 O                                                                         H    H    H                                           124   Pyrimidin-5-yl                                                                             OCH.sub.2                                                                          H    H    H                                           125   Pyrimidin-5-yl                                                                             NH   H    H    H                                           126   Pyrimidin-5-yl                                                                             N(CH.sub.3)                                                                        H    H    H                                           127   Pyrimidin-5-yl                                                                             S    H    H    H                                           128   Pyrimidin-5-yl                                                                             CH.sub.2                                                                           H    H    H                                           129   Pyrimidin-5-yl                                                                             CH(OH)                                                                             H    H    H                                           130   6-Chloropyridazin-                                                                         O    H    H    H                                                 3-yl                                                                    131   6-Chloropyridazin-                                                                         CH.sub.2 O                                                                         H    H    H                                                 3-yl                                                                    132   6-Chloropyridazin-                                                                         NH   H    H    H                                                 3-yl                                                                    133   6-Chloropyridazin-                                                                         N(CH.sub.3)                                                                        H    H    H                                                 3-yl                                                                    134   6-Chloropyridazin-                                                                         CH(OH)                                                                             H    H    H                                                 3-yl                                                                    135   Pyridazin-4-yl                                                                             O    H    H    H                                           136   Pyridazin-4-yl                                                                             OCH.sub.2                                                                          H    H    H                                           137   Pyridazin-4-yl                                                                             NH   H    H    H                                           138   Pyridazin-4-yl                                                                             SO.sub.2 O                                                                         H    H    H                                           139   1,3,5-Triazin-2-yl                                                                         NH   H    H    H                                           140   1,3,5-Triazin-2-yl                                                                         N(CH.sub.3)                                                                        H    H    H                                           141   1,2,4-Triazin-3-yl                                                                         O    H    H    H                                           142   1,2,4-Triazin-3-yl                                                                         NH   H    H    H                                           143   1,2,4-Triazin-3-yl                                                                         N(CH.sub.3)                                                                        H    H    H                                           144   1,2,4-Triazin-5-yl                                                                         O    H    H    H                                           145   1,2,4-Triazin-5-yl                                                                         NH   H    H    H                                           146   1,2,4-Triazin-6-yl                                                                         O    H    H    H                                           147   1,2,4-Triazin-6-yl                                                                         N(CH.sub.3)                                                                        H    H    H                                           148   Pyrimidin-2-yl,                                                                            O    H    H    H                                                  .sub.-- N-oxide                                                        149   Pyrimidin-4-yl, 1-                                                                         O    H    H    H                                                  .sub.-- N-oxide                                                        150   Pyrimidin-4-yl, 3-                                                                         O    H    H    H                                                  .sub.-- N-oxide                                                        151   Pyridin-2-yl,  .sub.-- N-oxide                                                             O    H    H    H                                           152   Pyridin-3-yl,  .sub.-- N-oxide                                                             O    H    H    H                                           153   Pyrazin-2-yl, 1- .sub.-- N-oxide                                                           O    H    H    H                                           154   Pyrazin-2-yl, 4- .sub.-- N-oxide                                                           O    H    H    H                                           155   Pyridazin-3-yl, 1- .sub.-- N-                                                              O    H    H    H                                                 oxide                                                                   156   Pyridazin-3-yl, 2- .sub.-- N-                                                              O    H    H    H                                                 oxide                                                                   157   Isoquinolin-1-yl                                                                           O    H    H    H                                           158   Isoquinolin-1-yl                                                                           NH   H    H    H                                           159   Isoquinolin-1-yl                                                                           CH.sub.2 O                                                                         H    H    H                                           160   Isoquinolin-1-yl                                                                           OCH.sub.2                                                                          H    H    H                                           161   Isoquinolin-1-yl                                                                           CH(OH)                                                                             H    H    H                                           162   Isoquinolin-1-yl                                                                           S    H    H    H                                           163   Isoquinolin-1-yl                                                                           SO.sub.2 O                                                                         H    H    H                                           164   Quinolin-4-yl                                                                              O    H    H    H                                           165   Quinolin-4-yl                                                                              NH   H    H    H                                           166   Quinolin-4-yl                                                                              CH.sub.2 O                                                                         H    H    H                                           167   Quinolin-4-yl                                                                              OCH.sub.2                                                                          H    H    H                                           168   Quinolin-4-yl                                                                              CH(OH)                                                                             H    H    H                                           169   Quinolin-4-yl                                                                              S    H    H    H                                           170   Quinolin-4-yl                                                                              SO.sub.2 O                                                                         H    H    H                                           171   Quinazolin-4-yl                                                                            O    H    H    H                                           172   Quinazolin-4-yl                                                                            NH   H    H    H                                           173   Quinazolin-4-yl                                                                            CH.sub.2 O                                                                         H    H    H                                           174   Quinazolin-4-yl                                                                            OCH.sub.2                                                                          H    H    H                                           175   Quinazolin-4-yl                                                                            CH(OH)                                                                             H    H    H                                           176   Quinazolin-4-yl                                                                            S    H    H    H                                           177   Quinazolin-4-yl                                                                            SO.sub.2 O                                                                         H    H    H                                           178   7-Chloroquinolin-4-yl                                                                      O    H    H    H                                           179   7-Chloroquinolin-4-yl                                                                      S    H    H    H                                           180   7-Chloroquinolin-4-yl                                                                      NH   H    H    H                                           181   Purin-6-yl   O    H    H    H                                           182   2-Chloropurin-6-yl                                                                         S    H    H    H                                           183   2-Chloropurin-6-yl                                                                         NH   H    H    H                                           184   5-NO.sub.2 -Thien-2-yl                                                                     OCH.sub.2                                                                          H    H    H                                           185   5-NO.sub.2 -Thien-2-yl                                                                     O    H    H    H                                           186   Thiazol-2-yl CH.sub.2 O                                                                         H    H    H                                           187   Thiazol-2-yl O    H    H    H                                           188   Thiazol-2-yl NH   H    H    H                                           189   Thiazol-4-yl CH.sub.2 O                                                                         H    H    H                                           190   Thiazol-4-yl O    H    H    H                                           191   Thiazol-4-yl NH   H    H    H                                           192   Thiazol-5-yl CH.sub.2 O                                                                         H    H    H                                           193   Thiazol-5-yl O    H    H    H                                           194   Thiazol-5-yl NH   H    H    H                                           195   Oxazol-2-yl  CH.sub.2 O                                                                         H    H    H                                           196   Oxazol-4-yl  O    H    H    H                                           197   Oxazol-5-yl  NH   H    H    H                                           198   5-CF.sub.3 -1,3,4-Thia-                                                                    O    H    H    H                                                 diazol-2-yl                                                             199   5-CF.sub.3 -1,3,4-Thia-                                                                    OCH.sub.2                                                                          H    H    H                                                 diazol-2-yl                                                             200   4-Cl-1,2,5-Thia-                                                                           O    H    H    H                                                 diazol-3-yl                                                             201                                                                                  ##STR17##   O    H    H    H                                           202                                                                                  ##STR18##   NH   H    H    H                                           203                                                                                  ##STR19##   N(CH.sub.3)                                                                        H    H    H                                           204   4-Cl-Pyrimidin-2-yl                                                                        O    H    H    H    7.58 92-96                             205   4-Br-Pyrimidin-2-yl                                                                        O    H    H    H                                           206   4-F-Pyrimidin-2-yl                                                                         O    H    H    H                                           207   4-CH.sub.3 -Pyrimidin-2-yl                                                                 O    H    H    H                                           208   4-CH.sub.3 O-Pyrimidin-2-yl                                                                O    H    H    H                                           209   4-CH.sub.3 CH.sub.2 O-Pyrimidin-                                                           O    H    H    H                                                 2-yl                                                                    210   4-NO.sub.2 -Pyrimidin-2-yl                                                                 O    H    H    H                                           211   4-Cyano-Pyrimidin-2-yl                                                                     O    H    H    H                                           212   4-CF.sub.3 -Pyrimidin-2-yl                                                                 O    H    H    H                                           213   4-C.sub.6 H.sub.5 -Pyrimidin-2-yl                                                          O    H    H    H                                           214   4-C.sub.6 H.sub.5 O-Pyrimidin-2-yl                                                         O    H    H    H                                           215   5-F-Pyrimidin-2-yl                                                                         O    H    H    H                                           216   5-CH.sub.3 -Pyrimidin-2-yl                                                                 O    H    H    H                                           217   5-CH.sub.3 O-Pyrimidin-2-yl                                                                O    H    H    H                                           218   5-CH.sub.3 CH.sub.2 O-Pyrimidin-                                                           O    H    H    H                                                 2-yl                                                                    219   5-NO.sub.2 -Pyrimidin-2-yl                                                                 O    H    H    H                                           220   5-Cyano-Pyrimidin-2-yl                                                                     O    H    H    H                                           221   5-CF.sub.3 -Pyrimidin-2-yl                                                                 O    H    H    H                                           222   5-C.sub.6 H.sub.5 -Pyrimidin-2-yl                                                          O    H    H    H                                           223   5-C.sub.6 H.sub.5 O-Pyrimidin-2-yl                                                         O    H    H    H                                           224   4,5-Di-Cl-Pyrimidin-                                                                       O    H    H    H                                                 2-yl                                                                    225   4,6-Di-Cl-Pyrimidin-                                                                       O    H    H    H                                                 2-yl                                                                    226   4-Cl-6-CH.sub.3 -Pyrimidin-                                                                O    H    H    H                                                 2-yl                                                                    227   4-Cl-5-CH.sub.3 O-Pyrimidin-                                                               O    H    H    H                                                 2-yl                                                                    228   2-F-Pyrimidin-4-yl                                                                         O    H    H    H                                           229   2-Br-Pyrimidin-4-yl                                                                        O    H    H    H                                           230   2-CH.sub.3 -Pyrimidin-4-yl                                                                 O    H    H    H                                           231   2-CH.sub.3 O-Pyrimidin-4-yl                                                                O    H    H    H                                           232   2-CH.sub.3 CH.sub.2 O-Pyrimidin-                                                           O    H    H    H                                                 4-yl                                                                    233   2-NO.sub.2 -Pyrimidin-4-yl                                                                 O    H    H    H                                           234   2-CH.sub.3 S-Pyrimidin-4-yl                                                                O    H    H    H                                           235   2-Cyano-Pyrimidin-4-yl                                                                     O    H    H    H                                           236   2-CF.sub.3 -Pyrimidin-4-yl                                                                 O    H    H    H                                           237   2-C.sub.6 H.sub.5 O-Pyrimidin-4-yl                                                         O    H    H    H                                           238   2-C.sub.6 H.sub.5 -Pyrimidin-4-yl                                                          O    H    H    H                                           239   6-F-Pyrimidin-4-yl                                                                         O    H    H    H                                           240   6-Br-Pyrimidin-4-yl                                                                        O    H    H    H                                           241   6-CH.sub.3 -Pyrimidin-4-yl                                                                 O    H    H    H                                           242   6-CH.sub.3 O-Pyrimidin-4-yl                                                                O    H    H    H                                           243   6-CH.sub.3 CH.sub.2 O-Pyrimidin-                                                           O    H    H    H                                                 4-yl                                                                    244   6-NO.sub.2 -Pyrimidin-4-yl                                                                 O    H    H    H                                           245   6-Cyano-Pyrimidin-4-yl                                                                     O    H    H    H                                           246   6-CF.sub.3 -Pyrimidin-4-yl                                                                 O    H    H    H                                           247   6-C.sub.6 H.sub.5 O-Pyrimidin-4-yl                                                         O    H    H    H                                           248   6-C.sub.6 H.sub.5 -Pyrimidin-4-yl                                                          O    H    H    H                                           249   5-F-Pyrimidin-4-yl                                                                         O    H    H    H                                           250   5-Cl-Pyrimidin-4-yl                                                                        O    H    H    H                                           251   5-Br-Pyrimidin-4-yl                                                                        O    H    H    H                                           252   5-CH.sub.3 -Pyrimidin-4-yl                                                                 O    H    H    H                                           253   5-CH.sub.3 O-Pyrimidin-4-yl                                                                O    H    H    H                                           254   5-CH.sub.3 CH.sub.2 O-Pyrimidin-                                                           O    H    H    H                                                 4-yl                                                                    255   5-NO.sub.2 -Pyrimidin-4-yl                                                                 O    H    H    H                                           256   5-Cyano-Pyrimidin-4-yl                                                                     O    H    H    H                                           257   5-CF.sub.3 -Pyrimidin-4-yl                                                                 O    H    H    H                                           258   5-C.sub.6 H.sub.5 O-Pyrimidin-                                                             O    H    H    H                                                 4-yl                                                                    259   5-C.sub.6 H.sub.5 -Pyrimidin-4-yl                                                          O    H    H    H                                           260   2-Cl-Pyrimidin-5-yl                                                                        O    H    H    H                                           261   2-CH.sub.3 -Pyrimidin-5-yl                                                                 O    H    H    H                                           262   2-F-Pyrimidin-5-yl                                                                         O    H    H    H                                           263   2-CH.sub.3 O-Pyrimidin-5-yl                                                                O    H    H    H                                           264   2-Cyano-Pyrimidin-5-yl                                                                     O    H    H    H                                           265   4-CH.sub.3 -Pyrimidin-5-yl                                                                 O    H    H    H                                           266   4-CH.sub.3 O-Pyrimidin-5-yl                                                                O    H    H    H                                           267   4-CF.sub.3 -Pyrimidin-5-yl                                                                 O    H    H    H                                           268   2,4-di-CH.sub.3 -Pyrimidin-                                                                O    H    H    H                                                 5-yl                                                                    269   2-CH.sub.3 S-4-CH.sub.3 O-                                                                 O    H    H    H                                                 Pyrimidin-5-yl                                                          270   Pyrrol-2-yl  CONH H    H    H                                           271   6-Cl-3-NO.sub.2 -Pyridin-                                                                  O    H    H    H                                                 2-yl and                                                                      6-Cl-5-NO.sub.2 -Pyridin-                                                     2-yl, 1:1 mixture                                                       272   3,6-Di-CH.sub.3 -Pyrazin-2-                                                                O    H    H    H                                                 yl                                                                      273   6-Cl-Pyrazin-2-yl                                                                          O    H    H    H                                           274   6-CH.sub.3 O-Pyridazin-3-yl                                                                O    H    H    H                                           275   6-Cl-4-CH.sub.3 -Pyridazin-                                                                O    H    H    H                                                 3-yl                                                                    276   6-Cl-5-CH.sub.3 -Pyridazin-                                                                O    H    H    H                                                 3-yl                                                                    277   4-CF.sub.3 -Pyridin-2-yl                                                                   O    H    H    H                                           278   6-Cyanopyridin-2-yl                                                                        O    H    H    H                                           279   4-Cyanopyridin-2-yl                                                                        O    H    H    H                                           280   4-Acetylpyridin-2-yl                                                                       O    H    H    H                                           281   6-C.sub.6 H.sub.5 -Pyridazin-3-yl                                                          O    H    H    H                                           282   3-(CH.sub.3 O.sub.2 C)-Pyridin-2-yl                                                        O    H    H    H                                           283   5-(CH.sub.3 O.sub.2 C)-Pyridin-3-                                                          O    H    H    H                                                 yl                                                                      284   4-CF.sub.2 Cl-Pyridin-2-yl                                                                 O    H    H    H                                           285   3,5-Di-CF.sub.3 -Pyridin-2-                                                                O    H    H    H                                                 yl                                                                      286   6-CF.sub.3 -Pyridin-2-yl                                                                   O    H    H    H                                           287   5-CF.sub.3 -Pyridin-3-yl                                                                   O    H    H    H                                           288   2-Cl-Pyridin-3-yl                                                                          O    H    H    H                                           289   2-CH.sub.3 O-Pyridin-3-yl                                                                  O    H    H    H                                           290   2-Cl-Pyridin-4-yl                                                                          O    H    H    H                                           291   2-CH.sub.3 O-Pyridin-4-yl                                                                  O    H    H    H                                           292   2-Cl-Pyridin-5-yl                                                                          O    H    H    H                                           293   2-CH.sub.3 O-Pyridin-5-yl                                                                  O    H    H    H                                           294   3-CH.sub.3 S-Pyridin-2-yl                                                                  O    H    H    H                                           295   4-CF.sub.3 O-Pyridin-2-yl                                                                  O    H    H    H                                           296   4-CON(CH.sub.3).sub.2 -Pyridin-                                                            O    H    H    H                                                 2-yl                                                                    297   3-Cl-1,2,4-Oxa-                                                                            O    H    H    H                                                 diazol-5-yl                                                             298   3-Cl-1,2,4-Oxa-                                                                            S    H    H    H                                                 diazol-5-yl                                                             299   5-CH.sub.3 S-1,2,4-Oxa-                                                                    O    H    H    H                                                 diazol-3-yl                                                             300   Pyridin-2-yl CH(OH)                                                                             H    H    H                                           301   Pyridin-3-yl CH(OH)                                                                             H    H    H                                           302   Pyridin-4-yl CH(OH)                                                                             H    H    H                                           303   Pyridin-2-yl CO   H    H    H                                           304   Pyridin-3-yl CO   H    H    H                                           305   Pyridin-4-yl CO   H    H    H                                           306   Thien-2-yl   CH(OH)                                                                             H    H    H                                           307   Furan-2-yl   CH(OH)                                                                             H    H    H                                           308    .sub.-- N-CH.sub.3 -Pyrrol-2-yl                                                           CH(OH)                                                                             H    H    H                                           309    .sub.-- N-CH.sub.3 -Pyrrol-2-yl                                                           CO   H    H    H                                           310   6-Br-Pyridin-2-yl                                                                          OCH.sub.2                                                                          H    H    H                                           311   2-Cl-Pyrimidin-4-yl                                                                        OCH.sub.2                                                                          H    H    H                                           312   2,6-Di-F-Pyrimidin-4-yl                                                                    O    H    H    H                                           313   2-CH.sub.3 S-6-CH.sub.3 -                                                                  O    H    H    H                                                 Pyrimidin-4-yl                                                          314   2-CH.sub.3 S-Pyrimidin-4-yl                                                                O    H    H    H                                           315    .sub.-- NCH.sub.3 -Pyrrol-2-yl                                                            CON  H    H    H                                                              (CH.sub.3)                                                 316   5-CF.sub.3 -Pyridin-2-yl                                                                   NH   H    H    H                                           317   2-Cl-Pyrimidin-4-yl                                                                        NH   H    H    H                                           318   4-Cl-Pyrimidin-2-yl                                                                        NH   H    H    H                                           319   5-NO.sub.2 -6-(CH.sub.3).sub.2 N-                                                          O    H    H    H                                                 Pyridin-2-yl                                                            320   3-NO.sub.2 -Pyridin-2-yl                                                                   O    H    H    H    7.59 128-130                           321   5-NO.sub.2 -Thiazol-2-yl                                                                   O    H    H    H    7.60 Gum                               322   2-CH.sub.3 SO.sub.2 -Pyrimidin-4-yl                                                        O    H    H    H    7.59 Foam                              __________________________________________________________________________     FOOTNOTES:                                                                    .sup.+ Chemical shift of singlet from olefinic proton on                      betamethoxypropenoate group (p.p.m from tetramethylsilane).                   Solvent: CDCl.sub.3 unless otherwise stated.                             

                  TABLE III                                                       ______________________________________                                         ##STR20##                                                                    ______________________________________                                    

Table III comprises 447 compounds of the general structure above withall the values of D, G, X, A, B and E listed in Table I. That is,Compound Nos. 1 to 447 of Table III are the same as those of Table Iexcept that the value of K is oxygen in Table I and sulphur in TableIII.

                  TABLE IV                                                        ______________________________________                                         ##STR21##                                                                    ______________________________________                                    

Table IV comprises 322 compounds of the general structure above with allthe values of Z, X, A, B and E listed in Table II. That is, compoundsNos. 1 to 322 of Table IV are the same as those of Table II except thatthe value of K is oxygen in Table II and sulphur is Table IV.

TABLE V: SELECTED PROTON NMR DATA

Table V shows selected proton n.m.r data for certain compounds describedin Tables I, II, III and IV. Chemical shifts are measured in p.p.m fromtetramethylsilane, and deuterochloroform was used as solvent throughout.The column headed `frequency` refers to the operating frequency of then.m.r spectrometer. The following abbreviations are used:

br=broad

s=singlet

d=doublet

t=triplet

q=quarter

m=multiplet______________________________________ COM-TABLE POUNDFREQUENCYNO. NO. (MHz)______________________________________I 21 2703.68(3H, s); 3.85 (3H, s); 5.08(2H, s); 6.90- 7.40(m); 7.58 (1H, s);7.63(1H, m); 8.12(1H, m)ppm.I 128 270 3.67(3H, s); 3.82(6H, s);6.68-7.28(9H, m); 7.57(1H, s); 7.61(1H, d); 8.23(1H, d)ppm.I 134 2703.69(3H, s); 3.85(3H, s); 6.83-7.17(6H, m); 7.34-7.52(2H, m); 7.58 (1H,s); 7.64(2H, m); 8.14(1H, m)ppm.I 447 270 3.66(3H, s); 3.78(2H, br s);3.84(3H, s); 6.67-7.30(9H, m); 7.57 (1H, s); 7.60(1H, m); 8.19(1H,m)ppm.II 6 270 3.68(3H, s); 3.85(3H, s); 5.38(2H, s); 6.75- 6.87(1H, m);6.98-7.06 (1H, m); 7.17-7.25(4H, m); 7.32-7.40(1H, m); 7.58(1H, s);7.55-7.64 (2H, m); 8.09-8.17(2H, m) ppm.II 321 270 3.70(3H, s); 3.86(3H,s); 7.05-7.15(4H, m); 7.44-7.50(1H, t); 7.60 (1H, s); 7.64-7.68(1H, m);8.12-8.15(2H, m) ppm.II 322 270 3.21(3H, s); 3.70(3H, s); 3.84(3H, s);6.90- 7.10(5H, m); 7.39-7.47 (1H, 5); 7.56-7.70(1H, m); 7.59(1H, s);8.12 (1H, m); 8.74(1H, d) ppm.______________________________________

The compounds of the invention of formula (I) can be made by a varietyof methods, and some of these are illustrated in Schemes I to VI.Throughout these Schemes, the terms K, Z, X, A, B, E, R¹, R², R³, R⁴ andR⁵ are as defined above, R⁶ is hydrogen or a metal (such as sodium orpotassium), R is an alkyl group, and L is a leaving group such as ahalide (chloride, bromide or iodide), a CH₃ SO₄ -anion, or asulphonyloxyanion. Each of the transformations described in Schemes I toVI is performed at a suitable temperature and either in a suitablesolvent or in the absence of a solvent.

Scheme I illustrates ways in which the methyl beta-methoxypropenoategroup can be constructed in the final stages of the preparation of thecompounds of the invention from precursors with a preformed framework of3 aromatic rings. Alternatively, the methyl beta-methoxy-propenoategroup may be constructed at an earlier stage of the preparation, inwhich case the final step or steps comprise elaboration of other partsof the compounds of the invention to form the framework of 3 aromaticrings. Examples of procedures of this kind are shown in Schemes II toVI.

In whichever order the steps are carried out to prepare the compounds ofthe invention, the ether linkage which is common to all the compounds ofthe invention can be prepared by one of the coupling reactions shown inScheme II. For a review of the Ullman ether synthesis see A. A. Morozand M. S. Shrartsberg, Russian Chem. Reviews, 1974, 43, 679. Thesecouplings are often performed in the presence of a catalyst whichconsists of a transition metal or a salt or compound of a transitionmetal, such as copper or a copper salt or compound, or a mixturethereof. In Scheme II, the term W represents either the group Z--X--,wherein Z and X are as defined above, or a group which can be convertedby standard procedures described in the chemical literature into thegroup Z--X--. For example, W can be OH, SH, or --NHR⁴. The term Yrepresents either the alpha-linked methyl beta-methoxypropenoate groupof the compounds of the invention or a group which can be converted intosuch a group by standard methods described in the chemical literatureand/or described in Scheme I and the following paragraphs. For example,Y can be --CH₂ CO₂ H, --CH₂ CO₂ Me or --CHO. In the context of SchemeII, the term L is preferably a halogen. Thus compounds of formula (XI)react with compounds of formula (XII) under the conditions of theUllmann reaction already described to give the intermediates of formula(VIII). As an example of one of the coupling reactions shown in SchemeII, substituted 3-phenoxyphenols, as their salts, undergo coupling with2-bromo- or 2-chloro-3-cyanopyridine to give, substituted2-(3-phenoxyphenoxy)-3-cyanopyridines.

In one particular aspect, the invention includes a process for thepreparation of the compound of formula (I) which comprises reacting acompound of general formula (XIIa): ##STR22## wherein Y' is halogen orother good leaving group (e.g. C₁₋₄ alkylsulphonyl, optionallysubstituted aryl(suitably phenyl)sulphonyl and nitro), with a phenol orthiophenol of general formula (XIa): ##STR23## in the presence of abase, or with a salt of the phenol or thiophenol (XIa), preferably inthe presence of a catalyst which comprises a suitable transition metal,a transition metal salt or compound or a mixture thereof.

The compounds of the invention of formula (I) can be prepared from thepyridylacetates of formula (III) or the ketoesters of formula (VI) bythe steps shown in Scheme I.

Thus compounds of formula (I) can be prepared by treatment ofpyridylacetates of formula (III) with a base (such as sodium hydride orsodium methoxide) and methyl formate. If a species of formula CH₃ L,wherein L is as defined above, is then added to the reaction mixture,compounds of formula (I) may be obtained. If a protic acid is added tothe reaction mixture, compounds of formula (II) wherein R⁵ is hydrogenare obtained. Alternatively, the species of formula (II) wherein R⁵ is ametal (such as sodium) may themselves be isolated from the reactionmixture.

Compounds of formula (II) wherein R⁵ is a metal can be converted intocompounds of formula (I) by treatment with a species of formula CH₃ L,wherein L is as defined above. Compounds of formula (II) wherein R⁵ ishydrogen can be converted into compounds of formula (I) by successivetreatments with a base (such as potassium carbonate) and a species ofgeneral formula CH₃ L.

Alternatively, compounds of formula (I) can be prepared from acetals offormula (IV) by elimination of methanol under either acidic or basicconditions. Examples of reagents or reagent mixtures which can be usedfor this transformation are lithium di-isopropylamide; potassiumhydrogen sulphate (see, for example T Yamada, H Hagiwara and H Uda, J.Chem. Soc., Chemical Communications, 1980, 838, and references therein);and triethylamine, often in the presence of a Lewis acid such astitanium tetrachloride (see, for example, K Nsunda and L Heresi, J.Chem. Soc., Chemical Communications, 1985, 1000).

Acetals of formula (IV) can be prepared by treatment of methyl silylketene acetals of formula (V) wherein R is an alkyl group, withtrimethyl orthoformate in the presence of a Lewis acid such as titaniumtetrachloride (see, for example, K Saigo, M Osaki and T Mukaiyama,Chemistry Letters, 1976, 769).

Methyl silyl ketene acetals of formula (V) can be prepared frompyridylacetates of formula (III) by treatment with a base and atrialkylsilyl halide of formula R₃ SiCl or R₃ SiBr, such astrimethylsilyl chloride, or a base (such as triethylamine) and atrialkylsilyl triflate of formula R₃ Si--OSO₂ CF₃ (see, for example, CAinsworth, F Chen and Y Kuo, J. Organometallic Chemistry, 1972, 46, 59).

It is not always necessary to isolate the intermediates (IV) and (V);under appropriate conditions, compounds of formula (I) may be preparedfrom pyridylacetates of formula (III) in "one pot" by the successiveaddition of suitable reagents listed above.

Alternatively, compounds of formula (I) can be prepared by treatment ofketoesters of formula (VI) with, for example,methoxymethylenetriphenylphosphorane (see, for example, W Steglich, GSchramm, T Anke and F Oberwinkler, EP 0044448, 4.7.1980).

Ketoesters of formula (VI) may be prepared by methods described in theliterature. Particularly useful methods include (i) the reaction ofappropriate pyridylmagnesium halides or pyridyl-lithium species withdimethyl oxalate using the method described by L M Weinstock R B Currieand A V Lovell, Synth. Commun., 1981, 11, 943 and references therein;(ii) oxidation of pyridylacetates of formula (III) using seleniumdioxide, generally in the absence of a solvent, and generally at atemperature above 100° C.; and (iii) oxidation of (3-pyridyl)glycolicacid esters using, for example, manganese oxide in a suitable solvent.

Pyridylacetates of formula (III) and the corresponding pyridylaceticacids of formula (VII) may also be prepared by numerous other methodsdescribed int he chemical literature. For example, several usefulmethods are described by D C Atkinson, K E Godfrey, B Meek, J F Savilleand M R Stillings, J. Med. Chem., 1983, 26, 1353 and D C Atkinson, K EGodfrey, P L Meters, N C Phillips, M R Stillings and A P Welbourn, J.Med. Chem., 1983, 26, 1361. Furthermore, many of the methods describedfor the preparation of 2-arylpropionic esters and acids by J-P Rieu, ABoucherle, H Cousse and G Mouzin, Tetrahedron, 1986, 42, 4095, are alsoapplicable to the preparation of pyridylacetates of formula (III) andpyridylacetic acids of formula (VII) using appropriate precursorswherein the ortho-substituted phenoxy substituent and the substituent Eare already present. ##STR24##

Schemes III, IV, V, VI and VII illustrate examples of intermediatescontaining the methyl beta-methoxypropenoate group and show how they maybe converted into certain specific types of compound of the invention(I).

Thus, in Scheme III, in the presence of a base, and sometimes in thepresence of a transition metal or transition metal salt catalyst, suchas a copper to copper salt catalyst, compounds of formula (XIII) reactwith aromatic or heteroaromatic compounds of formula ZL, wherein Z and Lare as defined above, or with iodonium salts of formula Z₂ I⁺ T⁻,wherein Z is as defined as above and T is a counter ion, such as ahalide ion, or with aryl or heteroarylbismuth species, to give compoundsof formula (XIV). In addition, in the presence of a base, compounds offormula (XIII) react with aryl- or heteroarylsulphonyl halides offormula ZSO₂ Q, wherein Z is as defined above and Q is a halogen, togive compounds of formula (XV). Furthermore, and also in the presence ofa base, compounds of formula (XIII) react with arylalkyl orheteroarylalkyl species of formula ZCHR¹ L, wherein Z, R¹ and L are asdefined above, to give compounds of formula (XVI).

In Scheme IV the thiols of formula (XVII), generally in the presence ofa base, react with aromatic or heteroaromatic compounds of formula ZL,or with iodonium salts of formula Z₂ I⁺ T⁻, or with aryl- orheteroarylbismuth species, to give compounds of formula (XVIII) in wayswhich are analogous to the reactions of the corresponding phenols offormula (XIII). Similarly, and again in the presence of a base, thethiols of formula (XVII) react with arylalkyl or heteroarylalkyl speciesof formula ZCHR¹ L to give compounds of formula (XIX). The sulphides offormula (XVIII) and (XIX) can be oxidised to the correspondingsulphoxides and sulphones by standard methods described in the chemicalliterature.

In Scheme V, compounds of formula (XX) react with hydroxy-derivatives ofaromatic or heteroaromatic compounds of formula ZOH, wherein Z is asdefined above, often in the presence of a base, to form compounds offormula (XXI). Further more, compounds of formula (XX) react withtrialkylphosphites of formula P(OR)₃ or with species of formula M⁺ P⁻(O)(OR)₂, wherein R is as defined above in each case and M is a metalsuch as sodium or lithium, to give phosphonates of formula (XXII).Phosphonates of formula (XXII), in the presence of a base, react withaldehydes or ketones of formula ZR¹ C:O, wherein Z and R¹ are as definedabove, to give olefins of formula (XXIV). In addition, aldehydes orketones of formula (XXIII), on treatment with phosphonate anions offormula ZR¹ C⁻ P(O)(OR)₂ M⁺, wherein Z, R, R¹ and M are as definedabove, or with the corresponding phosphoranes, also give olefins offormula (XXIV). The olefins of formula (XXIV) can be reduced to thecompounds of formula (XXV) by, for example, hydrogenation over anappropriate catalyst.

In Scheme VI, compounds of formula (XXVI), in the presence of a base,react with acid halides of formula ZCOQ, wherein Z and Q are as definedabove, or, in the presence of an appropriate dehydrating agent, reactwith acids of formula ZCO₂ H, wherein Z is as defined above, to givecompounds of formula (XXVII).

Intermediates of formula (XXVI) can also be converted into other typesof compound of the invention of formula (I) by methods described in thechemical literature. For example, compounds of formula (XXVI) wherein R⁴is hydrogen can be converted, via diazotisation, into the correspondingsulphonyl chlorides (compare Organic Syntheses, 1981, 60, 121) and then,by treatment with alcohols or phenols in the presence of a base intosulphonic esters.

Compounds of the invention of formula (I) wherein at least one of A andB are hydrogen may be converted into compounds of the invention offormula (I) wherein at least one of A and B are certain substituents(such as a halogen or a nitro or acyl group) by electrophilicsubstitution processes of the kind described in the chemical literature.

The intermediates of formulae (XIII), (XVII), (XX), (XXIII) and (XXVI)can be prepared by processes described in the chemical literature and byprocesses of the kinds described in Schemes I and II. For example,compounds of formula (XX) where L is bromine can be made from compoundsof formula (XX) where L is H, by reaction with N-bromosuccinimide orN,N-dibromodimethylhydantoin, in the presence or absence of irradiationby light.

The intermediates of formulae (IX), (X), (XI), (XII), ZL, Z₂ I⁺ T⁻,ZCHR¹ L, ZSO₂ Q, ZOH, ZR¹ C:O, ZR¹ C⁻ P(O)(OR)₂ M⁺, ZCOQ and ZCO₂ H canbe made by methods described in the chemical literature. ##STR25##

In Scheme VII compounds of formula (XXVIII) can be oxidised, for exampleusing pyridinium dichromate in a suitable solvent (such as methylenechloride) or oxalyl chloride in dimethyl sulphoxide in the presence of abase (the Swern oxidation), to give aldehydes (where R² is H) or ketones(where R² is alkyl) of formula (XXIII). The aldehydes or ketones offormula (XXIII) can react with oxyamines of formula ZONH₂ or ZCHR¹ ONH₂,or with hydrazines of formula ZNR¹ NH₂, wherein Z and R¹ are as definedabove, to give compounds of the invention of formula (I) where X is thegroup ON═CR², CHR¹ ON═CR², or NR¹ N═CR² respectively. Also, compounds offormula (XXIII) can react with Grignard reagents of formula ZMgHal orZCR¹ R² MgHal, where Hal is chlorine, bromine or iodine and Z, R¹ and R²are as defined above, to give compounds of the invention of formula (I)where X is CR² (OH) or CR¹ R² CR² (OH) respectively. Also, compounds offormula (XXIII) can react with amines of formula ZNHR¹ or ZCR¹ R² NHR¹,wherein Z, R¹ and R² are as defined above, in the presence of a reducingagent (such as sodium cyanoborohydride or hydrogen gas in the presenceof a suitable metal catalyst) to give compounds of the invention offormula (I) where X is NR¹ CHR² or CR¹ R² NR¹ CHR². When the reducingagent is left out and when R¹ is H, then the immediately precedingprocedure will give compounds of the invention of formula (I) where X isN═CR² or CR¹ R² N═CR².

Compounds of formula (XXVIII) where R² is H, can also be oxidised tocarboxylic acids of formula (XXIX), using for example Jones' reagent(chromium trioxide in sulphuric acid). The carboxylic acids (XXIX) canbe converted directly into compounds of the invention of formula (I)where, for example, X is O₂ C, CHR¹ OCO, SCO, CHR¹ SCO, NR⁴ CO or CHR¹NR⁴ CO, using one of the standard coupling reagents well known in theliterature, such as dicyclohexylcarbodiimide or carbonyldiimidazole, ina suitable solvent.

Alternatively, the carboxylic acids of formula (XXIX) can be convertedinto the acid chlorides of formula (XXX) by treatment with, for example,thionyl chloride or oxalyl chloride. The acid chlorides of formula (XXX)can then react, for example, with compounds of formula ZOH, ZCHR¹ OH,ZSH, ZCHR¹ SH, ZNR⁴ H or ZCHR¹ NR⁴ H in a suitable solvent, in thepresence of a base, to give compounds of the invention of formula (I)where X is O₂ C, CHR¹ OCO, SCO, CHR¹ SCO, NR⁴ CO, or CHR¹ NR⁴ COrespectively.

Compounds of formula (XXVIII) can also react directly with compounds offormula ZL, optionally in the presence of a base, where Z is a reactivearomatic group (for example nitrophenyl) or heteroaromatic group (forexample 2-pyridyl or 2-pyrimidinyl) to give compounds of the inventionof formula (XXI). It may be necessary first to generate the oxygen anionof compounds of formula (XXVIII) with a strong base such as sodiumhydride.

Additionally, compounds of formula (XXVIII) can be converted intocompounds of formula (XX) by treatment, for example, with a halogenationagent such as thionyl chloride or phosphorus tribromide, where L ischlorine or bromine, or by treatment with a sulphonyl halide (such asp-toluenesulphonyl chloride) in the presence of an acid acceptor, whereL is a sulphonyloxy group. Compounds of formula (XX) can then be used asshown in Scheme V. Additionally, where L is halogen, they can beconverted by reaction with a phosphine of formula Z(R⁵)₂ P, wherein R⁵is as defined above, into compounds of the invention of formula (I),where X is the group (R⁵)₂ P⁺ CHR² Z⁻. These compounds can then reactsuccessively with a base and a carbonyl compound of formula ZCOR¹,wherein Z and R¹ are as defined above, to give olefins of formula(XXIV).

Scheme VIII illustrates examples of intermediates of formula (VIII),shown in Scheme II, where W is any group that can be converted to ZX-,and Y is any group that can be converted to the methylbeta-methoxypropenoate group.

Compounds of formula (XXXI) can react with compounds of formula (XXXII)to give compounds of formula (XXXIII), using the general Ullmanncoupling conditions described in detail for the reaction of compounds offormula (XI) and (XII) in Scheme II. The acids of formula (XXXIII) canbe converted into methyl esters of formula (XXXIV) by reaction withmethanol in the presence of acid (for example hydrochloric acid).Compounds of formula (XXXIV) can then be converted into methylbeta-methoxypropenoates of formula (XXVIII) by the methods described indetail in Scheme I.

Alternatively, the intermediates of formula (XXXIV) can be convertedinto intermediates of formulae (XXXVIII), (XXXV), (XXXVI), (XXXVII) and(III) using the methods described in Scheme VII for the conversion ofthe propenoates of formula (XXVIII) into compounds of formula (XXIII),(XX), (XXIX), (XXX) and (I). Compounds of formula (III) can be convertedinto compounds of formula (I) as shown in Scheme I. ##STR26##

In a further aspect the invention provides processes as hereindescribedfor preparing the compounds of formula (I). It also providesintermediate chemicals for formulae (II)-(VII) and (XIII)-(XXX), and(XXXIII)-(XXXVIII).

The compounds are active fungicides and may be used to control one ormore of the following pathogens:

Pyricularia oryzae on rice.

Puccinia recondita, Puccinia striiformis and other rust on wheat,Puccinia hordei, Puccinia striiformis and other rusts on barley, andrusts on other hosts, e.g. coffee, pears, apples, peanuts, vegetablesand ornamental plants.

Erysiphe graminis (powdery mildew) on barley and wheat and other powderymildews on various hosts such as Sphaerotheca macularis on hops,Sphaerotheca fuliginea on cucurbits (e.g. cucumber), Podosphaeraleucotricha on apple and Uncinula necator on vines. Helminthosporiumspp., Rhynchosporium spp., Septoria spp., Pseudocercosporellaherpotrichoides and Gaeumannomyces graminis on cereals. Cercosporaarachidicola and Cercosporidium personata on peanuts and otherCercospora species on other hosts, for example, sugar beet, bananas,soya beans and rice.

Botrytis cinerea (grey mould) on tomatoes, strawberries, vegetables,vines and other hosts.

Alternaria species on vegetables (e.g. cucumber), oil seed rape, apples,tomatoes and other hosts.

Venturia inaequalis (scab) on applies.

Plasmopara viticola on vines.

Other downy mildews such as Bremia lactucae on lettuce, Peronospora spp.on soya beans, tobacco, onions and other hosts and Pseudoperonosporahumuli on hops and Pseudoperonospora cubensis on cucurbits Phytophthorainfestans on potatoes and tomatoes and other Phytophthora spp. onvegetables, strawberries, avocado, pepper, ornamentals, tobacco, cocaand other hosts.

Thanatephorus cucumeris on rice and other Rhizoctonia species on varioushost such as wheat and barley, vegetables, cotton and turf.

Some of the compounds show a broad range of activities against fungi invitro. They may also have activity against various post-harvest diseasesof fruit (e.g. Penicillium digitatum and italicum and Trichoderma virideon oranges, Gloesporium musarum and bananas and Botrytis cinerea ongrapes).

Further some of the compounds may be active as seed dressings againstFusarium spp., Septoria spp., Tilletia spp., (bunt, a seed borne diseaseof wheat), Ustilago spp. Helminthosporium spp. on cereals, Rhizoctoniasolani on cotton and Pyricularia oryzae on rice.

The compounds may have systemic movement in plants. Moreover, thecompounds may be volatile enough to be active in the vapour phaseagainst fungi on the plant.

The invention therefore provides a method of combating fungi, whichcomprises applying to a plant, to seed of a plant, or tot he locus ofthe plant or seed, an effective amount of compound as hereinbeforedefined, or a composition containing the same.

The compounds may also be useful as industrial (as opposed toagricultural) fungicides, e.g. in the prevention of fungal attack onwood, hides, leather and especially paint films.

The compounds may be used directly for fungicidal purposes but are moreconveniently formulated into compositions using a carrier or diluent.The invention thus provides a fungicidal composition comprising acompound of general formula (I) as hereinbefore defined, and afungicidally acceptable carrier or diluent.

Used as fungicides, the compounds can be applied in a number of ways.For example they can be applied, formulated or unformulated, directlytot he foliage of a plant, to seeds or to other medium in which plantsare growing or are to be planted, or they can be sprayed on, dusted onor applied as a cream or paste formulation, or they can be applied as avapour or as slow release granules. Application can be to any part ofthe plant including the foliage, stems, branches or roots, or to soilsurrounding the roots, or to the seed before it is planted; or to thesoil generally, to paddy water or to hydroponic culture systems. Theinvention compounds may also be injected into plants or sprayed ontovegetation using electrodynamic spraying techniques or other low volumemethods.

The term "plant" as used herein includes seedlings, bushes and trees.Furthermore, the fungicidal method of the invention includespreventative, protectant, prophylactic and eradicant treatment.

The compounds are preferably used for agricultural and horticulturalpurposes in the form of a composition. The type of composition used inany instance will depend upon the particular purpose envisaged.

The compositions may be in the form of dustable powders or granulescomprising the active ingredient (invention compound) and a soliddiluent or carrier, for example fillers such as kaolin, bentonite,kiesselguhr, dolomite, calcium carbonate, talc, powdered magnesia,Fuller's earth, gypsum, diatomaceous earth and China clay. Such granulescan be performed granules suitable for application to the soil withoutfurther treatment. These granules can be made either by impregnatingpellets of filler with the active ingredient or by pelleting a mixtureof the active ingredient and powdered filler. Compositions for dressingseed may include an agent (for example a mineral oil) for assisting theadhesion of the composition to the seed; alternatively the activeingredient can be formulated for seed dressing purposes using an organicsolvent (for example N-methylpyrrolidone, propylene glycol ordimethylformamide). The compositions may also be int he form of wettablepowders of water dispersible granules comprising wetting or dispersingagents to facilitate the dispersion in liquids. The powders and granulesmay also contain fillers and suspending agents.

Emulsifiable concentrates or emulsions may be prepared by dissolving theactive ingredient in an organic solvent optionally controlling a wettingor emulsifying agent and then adding the mixture to water which may alsocontain a wetting or emulsifying agent. Suitable organic solvents arearomatic solvents such as alkylbenzenes and alkylnaphthalenes, ketonessuch as isophorone, cyclohexanone, and methylcyclohexanone, chlorinatedhydrocarbons such as chlorobenzene and trichlorethane, and alcohols suchas benzyl alcohol, furfuryl alcohol, butanol and glycol ethers.

Suspension concentrates of largely insoluble solids may be prepared byball or bead milling with a dispersing agent and including a suspendingagent to stop the solid settling.

Compositions to be used as sprays may be in the form of aerosols whereinthe formulation is held in a container under pressure int he presence ofa propellant, e.g. fluorotrichloromethane or dichlorodifluoromethane.

The invention compounds can be mixed in the dry state with a pyrotechnicmixture to form a composition suitable for generating in enclosed spacesa smoke containing the compounds.

Alternatively, the compounds may be used in micro-encapsulated form.They may also be formulated in biodegradable polymeric formulations toobtain a slow, controlled release of the active substance.

By including suitable additives, for example additives for improving thedistribution, adhesive power and resistance to rain on treated surfaces,the different compositions can be better adapted for various utilities.

The invention compounds can be used as mixtures with fertilisers (e.g.nitrogen-, potassium-, or phosphorus-containing fertilisers).Compositions comprising only granules of fertiliser incorporating, forexample coated with, the compound are preferred. Such granules suitablecontain up to 25% by weight of the compound. The invention thereforealso provides a fertiliser composition comprising a fertiliser and thecompound of general formula (I) or a salt or metal complex thereof.

Wettable powders, emulsifiable concentrates and suspension concentrateswill normally contain surfactants e.g. wetting agent, dispersing agent,emulsifying agent or suspending agent. These agents can be cationic,anionic or non-ionic agents.

Suitable cationic agents are quaternary ammonium compounds, for example,cetyltrimethylammonium bromide. Suitable anionic agents are soaps, saltsof aliphatic monoesters of sulphuric acid (for example sodium laurylsulphate), and salts of sulphonated aromatic compounds (for examplesodium dodecylbenzenesulphonate, sodium, calcium or ammoniumlignosulphonate, butylnaphthalene sulphonate, and a mixture of sodiumdiisopropyl- and triisopropyl-naphthalene sulphonates).

Suitable non-ionic agents are the condensation products of ethyleneoxide with fatty alcohols such as oleyl or cetyl alcohol, or with alkylphenols such as octyl- or nonyl-phenol and octylcresol. Other non-ionicagents are the partial esters derived from long chain fatty acids andhexitol anhydrides, the condensation products of the said partial esterswith ethylene oxide, and the lecithins. Suitable suspending agents arehydrophilic colloids (for example polyvinylpyrrolidone and sodiumcarboxymethylcellulose), and swelling clays such as bentonite orattapulgite.

Compositions for use as aqueous dispersions or emulsions are generallysupplied in the form of a concentrate containing a high proportion ofthe active ingredient, the concentrate being diluted with water beforeuse. These concentrates should preferably be able to withstand storagefor prolonged periods and after such storage be capable of dilution withwater in order to form aqueous preparations which remain homogeneous fora sufficient time to enable them to be applied by conventional sprayequipment. The concentrates may conveniently contain up to 95% suitable10-85%, for example 25-60%, by weight of the active ingredient. Afterdilution to form aqueous preparations, suitable preparations may containvarying amounts of the active ingredient depending upon the intendedpurpose, but an aqueous preparation containing 0.00055 or 0.01% to 10%by weight of active ingredient may be used.

The compositions of this invention may contain other compounds havingbiological activity, e.g. compounds having similar or complementaryfungicidal activity or which plant posses plant growth regulating,herbicidal or insecticidal activity.

A fungicidal compound which may be present in the composition of theinvention may be one which is capable of combating ear disease ofcereals (e.g. wheat) such as Septoria, Gibberella and Helminthosporiumspp., seed and soil-borne diseases and downy and powdery mildews ongrapes and powdery mildew and scab on apple, etc. By including anotherfungicide, the composition can have a broader spectrum of activity thanthe compound of general formula (I) alone. Further the other fungicidecan have a synergistic effect on the fungicidal activity of the compoundof general formula (I). Examples of fungicidal compounds which may beincluded int he composition of the invention are carbendazim, benomyl,thiophanate-methyl, thiabendazole, fuberidazole, etridazole,dichlofluanid, cymoxanil, oxadixyl, ofurace, metalaxyl, furalaxyl,benalaxyl, fosetyl-aluminium, fenarimol, iprodione, prothiocarb,procymidone, vinclozolin, penconazole, myclobutanil, propamocarb,diniconazole, pyrazophos, ethirimol, ditalimfos, tridemorph, triforine,nuarimol, triazbutyl, guazatine, triacetate salt of1,1'-iminodi(octamethylene)diguanidine, buthiobate, propiconazole,prochloraz, flutriafol, hexaconazole, (2RS,5RS)-5-(2,4-dichlorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-2-furyl-2,2,2-trifluoroethylether, cyproconazole, terbuconazole, pyrrolnitrin, 1-[(2RS,4RS; 2RS,4RS)-4-bromo-2-(2,4-dichlorophenyl)tetrahydrofur-furyl[-1H-1,2,4-triazole,5-ethyl-5,8-dihydro-8-oxo(1,3)-dioxolo (4,5-g)quinoline-7-carboxylicacid, (RS)-1-aminopropylphosphonic acid,3-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)quinazolin-4(3H)-one,fluzilazole, triadimefon, triadimenol, diclobutrazol, fenpropimorph,pyrifenox, fenpropidin, chlorozolinate, imazalil, fenfuram, carboxin,oxycarboxin, methfuroxam, dodemorph, BAS 454, blasticidin S,kasugamycin, edifenphos, Kitazin P, cycloheximide, phthalide,probenazole, isoprothiolane, tricyclazole,4-chloro-N-(cyano(ethoxy)methyl)benzamide, pyroquilon,chlorbenzthiazone, neoasozin, polyoxin D, validamycin A, mepronil,flutolanil, pencycuron, diclomezine, phenazin oxide, nickeldimethyldithio-carbamate, techlofthalam, bitertanol, bupirimate,etaconazole, hydroxyisoxazole, streptomycin, cyprofuram, biloxazol,quinomethionate, dimethirimol, 1-(2-cyano-2-methoxyiminoacetyl)-3-ethylurea, fenapanil, tolclofos-methyl, pyroxyfur, polyram, maneb, mancozeb,captafol, chlorothalonil, anilazine, thiram, captan, folpet, zineb,propineb, sulphur, dinocap, dichlone, chloroneb, binapacyl,nitrothalisopropyl, dodine, dithianon, fentin hydroxide, fentin acetate,tecnazene, quintozene, dicloran, copper containing compounds such ascopper oxychloride, copper sulphate and Bordeaux mixture, andorganomercury compounds.

The compounds of general formula (I) can be mixed with soil, peat orother rooting media for the protection of plants against seed-borne,soil-borne or foliar fungal diseases.

Suitable insecticides which may be incorporated in the composition ofthe invention include pirimicarb, dimethoate, demeton-s-methyl,formothion, carbaryl, isoprocarb, XMC, BPMC, carbofuran, carbosulfan,diazinon, fenthion, fenitrothion, phenthoate, chlorpyrifo, isoxathion,propaphos, monocrotophas, buprofezin, ethroproxyfen and cycloprothrin.

Plant growth regulating compounds are compounds which control weeds orseedhead formation, or selectively control the growth of less desirableplants (e.g. grasses).

Examples of suitable plant growth regulating compounds for use with theinvention compounds are the gibberellins (e.g. GA₃, GA₄ or GA₇), theauxins (e.g. indoleacetic acid, indolebutyric acid, naphthoxyacetic acidor naphthylacetic acid), the cytokinins (e.g. kinetin, diphenylurea,benzimidazole, benzyladenine or benzylaminopurine), phenoxyacetic acids(e.g. 2,4-D or MCPA), substituted benzoic acid (e.g. triiodobenzoicacid), morphactins (e.g. chlorfluoroecol), maleic hydrazide, glyphosate,glyphosine, long chain fatty alcohols and acids, dikegulac,paclobutrazol, fluoridamid, mefluidide, substituted quaternary ammoniumand phosphonium compounds (e.g. chloromequat chlorphonium ormepiquatchloride), ethephon, carbetamide, methyl-3,6-dichloroanisate,daminozide, asulam, abscisic acid, isopyrimol,1-(4-chlorophenyl)-4,6-dimethyl-2 -oxo-1,2-dihydropyridine-3-carboxylicacid, hydroxybenzonitriles (e.g. bromoxynil), difenzoquat,benzoylprop-ethyl 3,6-dichloropicolinic acid, fenpentezol, inabenfide,triapenthenol and tecnazene.

The following Examples illustrates the invention. Throughout theExamples, the term `ether` refers to diethyl ether, magnesium sulphatewas used to dry solutions, and solutions were concentrated under reducedpressure. Reactions involving air- or water-sensitive intermediates wereperformed under an atmosphere of nitrogen and solvents were dried beforeuse, where appropriate. Unless otherwise stated, chromatography wasperformed on a column of silica gel as the stationary phase. Whereshown, infrared and n.m.r. data are selective; no attempt s made to listevery absorption in all cases. ¹ H n.m.r. spectra were recorded usingCDC1₃ -solutions unless otherwise stated. The following abbreviationsare used throughout:

    ______________________________________                                        THF =   tetrahydrofuran    s =     singlet                                    DMF =    .sub.--N, .sub.--N-dimethylformamide                                                            d =     doublet                                    n.m.r. =                                                                              nuclear magnetic resonance                                                                       t =     triplet                                    IR =    infrared           m =     multiplet                                  m.p. =  melting point      br =    broad                                      ______________________________________                                    

This Example illustrates the preparation of (E)-methyl2-[2-(3-phenoxyphenoxy)pyrid-3-yl]-3-methoxypropenoate (Compound No. 446of Table I).

A mixture of potassium carbonate (5.53 g, 0.04 mol) and 3-phenoxyphenol(15 g, 0.08 mol) in DMF (60 ml) was heated at 80° C. with stirring for30 minutes. 2-Chloro-3-cyanopyridine (11.08 g, 0.08 mol) and copperbronze (0.8 g) were added and the resulting mixture heated at reflux for90 minutes. GC analysis indicated the formation of a single product(96%). The reaction mixture was cooled and filtered, and then pouredinto water (300 ml) and allowed to sand over the weekend. Theyellow-brown oily precipitate was extracted into dichloromethane anddried. The dichloromethane solution was then filtered and evaporated toyield crude 2-(3-phenoxyphenoxy)-3-cyano-pyridine (36.2 g, contaminatedwith DMF) which was used in the next stage without further purification.

Crude 2-(3-phenoxyphenoxy(-3-cyanopyridine (15 g) was stirred with Raneynickel alloy (15 g, 50:50) in refluxing 75% formic acid (200 ml) for 2hours. The reaction mixture was diluted with water and then extractedrepeatedly with ether. The combined ether extracts were dried, filteredand evaporated to give an orange oil. Filtration through a plug ofsilica (eluent hexane-ether 1:1) afforded2-(3-phenoxyphenoxy)-3-formylpyridine (3.03 g), infrared max. 1685 cm⁻¹.

To a stirred solution of the aldehyde (3.03 g, 0.01 mol) and methylmethylsulphinylmethyl sulphide (1.29 g, 0.01 mol) in dry THF (8 ml) atroom temperature was added dropwise a solution of Triton B (2.5 ml, 40%in methanol). The resultant solution was heated to reflux for 1 hour,cooled and then diluted with water. Extraction with dichloromethanefollowed by drying and evaporation yielded a yellow oil which wasdissolved in methanolic hydrogen chloride (100 ml) and allowed to standovernight. The methanol was evaporated and the residue treated withsaturated sodium bicarbonate solution and then extracted withdichloromethane. The combined organic extracts were dried, filtered andevaporated. The residue was chromatographed on silica gel (eluenthexane-ether, 1:1) to afford methyl2-(3-phenoxyphenoxy)pyrid-3-ylacetate (1.35 g) as a pale yellow oil;

¹ H NMR delta 3.68 (3H, s); 3.74 (2H, s); 6.74-6.88 (3H, m); 6.96-7.12(4H, m); 7.24-7.40 (3H, m); 7.56-7.60 (1H, m); 8.06-8.12 (1H, m);

Infrared max. 1735 cm⁻¹.

A solution of methyl 2-(3-phenoxyphenoxy)pyrid-3-yl acetate (0.64 g,0.0019 mol) and methyl formate (2.34 ml, 0.038 mol) in DMF (2 ml) wasadded dropwise over 15 minutes to a stirred suspension of petrol-washedsodium hydride (0.18 g, 0.0038 mol, 50% dispersion in oil) in DMF (10ml). The temperature was kept below 10° C. during the addition. Thereaction mixture effervesced vigorously and became yellow in colour. Thetemperature of the solution was allowed to rise to room temperature andstirring continued for 2 hours. The reaction mixture was poured intowater (100 ml), neutralised with dilute hydrochloric acid and thenextracted with ether (4×25 ml). The combined ether layers were washedwith water and brine, and then dried and evaporated. The resultingyellow oil (0.69 g) was dissolved in DMF (10 ml) and then stirred withpotassium carbonate (0.53 g) for 15 minutes. Dimethyl sulphate (0.17 ml)was then added in one portion and stirring continued for a further 4hours. The reaction mixture was then diluted with water (100 ml) andextracted with ether (4×25). The combined extracts were washed withwater and brine, dried, filtered and evaporated to afford an orange oil.Chromatography on silica gel (eluent 40-60 petrol-ether, 1:1) yielded asolid which on crystallisation from ethanol-petrol gave the titlecompound as a crystalline solid (0.32 g, 45%);

Melting point: 79°-81° C.;

¹ H NMR delta 3.64 (3H, s); 3.84 (3H, s); 6.72-6.84 (3H, m); 7.00-7.12(4H, m); 7.24-7.34 (3H, m); 7.52-7.60 (2H, m); 7.56 (1H, s); 8.08-8.14(1H, m);

Infrared max. 1710, 1640 cm⁻¹.

EXAMPLE 2

This Example illustrates the preparation of (E)-methyl2-[2-(3-benzyloxyphenoxy)pyridin-3-yl]-3-methoxypropenoate (Compound No.23 of Table I).

3-Methoxyphenol (124 g) and anhydrous potassium carbonate (69 g) wereheated together with stirring in dry DMF (500 ml) at 80° C. under anatmosphere of nitrogen. After 45 minutes, the greyish solution wascooled and 2-chloronicotinonitrile (138.5 g) and cooper bronze (10 g)were added (washed in with 100 ml DMF). The resulting brown reactionmixture was heated to 125°-130° C. After 21/2 hours, the reactionmixture was cooled and filtered to remove excess copper bronze andundissolved solid material. The resulting solution was added to water (3liters) and left to stand overnight. The resulting precipitate wasfiltered, washed with water then dissolved in ether. The ether solutionwas dried, filtered and evaporated to afford2-(3-methoxyphenoxy)-3-cyanopyridine as an off-white solid (203.5 g,90%).

Melting point : 66°-68° C.

Infrared max : 2232 cm⁻¹.

To a stirred solution of 2-(3-methoxyphenoxy)-3-cyanopyridine (5 g) dryTHF (25 ml) at -70° C. under nitrogen was added dropwisediisobutylaluminum hydride (27.6 ml of a 1.0M solution in toluene) over30 minutes. The mixture was stirred at -70° C. for a further 30 minutesthen allowed to warm to room temperature. After 4 hours, GC analysisindicated 30% reaction. The reaction mixture was cooled to -70° C. andtreated as before with a second batch of diisobutyl alumminium hydride(27.6 ml). After one hour at room temperature no starting materialremained (GC analysis). Dilute hydrochloric acid (50 ml) was added verycarefully (exotherm!). The resulting solution was stirred for a further30 minutes and then partitioned with ether. The aqueous layer wasfurther extracted (× 2) with ether. The ether combined layers weredried, filtered and evaporated to afford a yellow oil. Chromatography onsilica gel (eluent dichloromethane) gave 2-(3-methoxyphenoxy)-3-pyridinecarboxaldehyde (1.7 g, 33%) as white crystals.

Melting point : 76°-78° C.

Infrared max. 1694 cm⁻¹ : ¹ H NMR delta 3.83 (3H, s); 6.75-6.84 (3H);7.11-7.15 (1H); 7.33-7.38 (1H); 8.24-8.26 (1H); 8.35-8.38 (1H) ppm.

In a separate larger scale experiment2-(3-methoxyphenoxy)-3-cyanopyridine (45 g) was converted (in 3 batches)into 2-(3-methoxyphenoxy)-3-pyridinecarboxaldehyde (34 g, 75%).

To a stirred solution of 2-(3-methoxyphenoxy)-3-pyridinecarboxaldehyde(8.07 g) and methyl methylsulphinylmethyl sulphide (6.78 ml) in dry THF(20 ml) at room temperature under nitrogen was added dropwise Triton B(14 mls, 40% solution in methanol). After heating to reflux for 11/2hours GC analysis indicated the absence of starting material. Thereaction mixture was cooled to room temperature and dichloromethane (450ml) was added. The resultant solution was then dried, extracted withwater (3×100 ml). The organic layer was then dried, filtered andevaporated to give an orange oil (22.88 g) which was used in the nextstage without further purification. The orange oil was dissolved inmethanolic hydrogen chloride (from (300 ml) methanol and (35 ml) acetylchloride) stirred for 4 hours and left to stand at room temperature.After 2 days, the solvent was removed and the residue neutralised withsaturated sodium bicarbonate solution. The product was extracted intoethyl acetate and the resulting solution dried, filtered and evaporatedto afford crude methyl 2-(3-methoxyphenoxy)-3-pyridinyl acetate (15.88g, 90% pure by GC).

Infrared max. 1740 cm⁻¹ : ¹ H NMR (CDCl₃) inter alia delta 3.71 (3H, s);3.76 (2H); 3.95 (3H). In a separate experiment2-(3-methoxyphenoxy)-3-pyridinecarboxaldehyde (33.03 g) was convertedinto methyl 2-(3-methoxyphenoxy)-3-pyridinylacetate (28 g, 71% overall).

Methyl 2-(3-methoxyphenoxy)-3-pyridinylacetate (27.2 g) was heated at115° C. in 47% hydrobromic acid (249 ml) containinghexadecyltributylphosphonium bromide (5.6 g). After 3 hours, thesolution was cooled and potassium carbonate added until the pH of thesolution was ca. 6. The reaction mixture was extracted (× 5) with ethylacetate. The organic extracts were dried, filtered and evaporated togive a pale orange solid. The solid was then treated with methanolichydrogen chloride overnight (from methanol (500 ml) and acetyl chloride(50 ml)). The methanol was removed and the residue dissolved in water.The pH of the solution was adjusted to ca. pH6 with sodium bicarbonateand the solution extracted with ethyl acetate (× 3). The combinedorganic extracts were dried, filtered and evaporated. The resultingorgange solid residue was re-dissolved in dichloromethane and filteredthrough a plug of silica (eluent ether dichloromethane). Evaporationafforded methyl 2-(3-hydroxyphenoxy)-3-pyridinylacetate as a pale yellowsolid (13.28 g, 51%) which was used without further purification.

Methyl 2-(3-hydroxyphenoxy)-3-pyridinylacetate (0.8 g) and anhydrouspotassium carbonate (0.21 g) were stirred together in DMF under nitrogenat 70° C. After 20 minutes benzyl bromide (1.06 g) was added togetherwith copper bronze (cat.) and the reaction mixture heated to 100° C. for3 hours. GC analysis indicated 50% reaction. A second equivalent of bothpotassium carbonate and benzyl bromide was added and heating continuedat 100° C. for 2 hours. The reaction mixture was cooled to roomtemperature, filtered, diluted with water and extracted with ether (×3). The ether extracts were combined, dried, filtered and evaporated togive a brown oil. Chromatography on silica gel (eluent petroleum ether -ether, 50:50) afforded methyl 2-(3-benzyloxyphenoxy)-3-pyridinylacetateas a light yellow solid (0.5 g, 46%).

Infrared max. 1735 cm⁻¹ : ¹ H NMR (CDCl₃) inter alia delta 3.70 (3H, s);3.76 (2H, s); 5.04 (2H, s).

In a separate experiment, a further 0.3 g of product was obtained. Thetwo samples were combined for the next stage.

A solution containing methyl formate (2.84 ml) and methyl2-(3-benzyloxyphenoxy)-3-pyridinylacetate (0.8 g) in DMF (2 ml) wasadded dropwise to a stirred suspension of sodium hydride (0.22 g, 50%dispersion in oil, pre-washed with petroleum ether) in DMF (10 ml)(effervescence). The temperature was maintained below 10° C. during thecourse of the addition and then allowed to rise to room temperature.After stirring for a further 4 hours the reaction mixture was allowed tostand over the weekend. The reaction mixture was poured into water, justacidified with dilute hydrochloric acid and then extracted with ether (×3). The combined ether extracts were dried, filtered and evaporated togive a yellow oil (0.86 g). The oil was dissolved in DMF (10 ml) andtreated with potassium carbonate (0.64 g) and dimethyl sulphate (0.21ml) at room temperature. After stirring for 4 hours GC analysisindicated complete reaction. Water (100 ml) was added and the resultingsolution extracted with ether (3×25 ml). The combined ether extractswere washed with water then brine and dried. Filtration and evaporationgave an orange-brown oil. Chromatography on silica gel (eluent petroleumether-ether, 50:50) affored the title compound as a white solid (0.2 g,22%).

Melting point : 119°-122° C., mass spectrum m/e 391 (M⁺).

Infrared max. : 1705, 1640 cm⁻¹.

¹ H NMR (CDCl₃) delta : 3.68 (3H, s); 3.84 (3H, s); 5.03 (2H, s);6.66-6.80 (3H, m); 6.96-7.04 (1H, m); 7.20-7.42 (6H, m); 7.58 (1H, s);7.60-7.62 (1H, m); 8.08-8.12 (1H, m).

EXAMPLE 3

This Example illustrates the preparation of(E)-methyl-2-[2-(3-((3-nitrobenzenesulphonyloxy)phenoxy)pyridin-3-yl]-3-methoxypropenoate(Compound No. 296 of Table I).

A solution containing methyl 2-(3-hydroxyphenoxy)-3-pyridinylacetate (1g; prepared as described in Example 2) and methyl formate (4.68 ml) inDMF (5 ml) was added dropwise to a stirred suspension of sodium hydride(0.55 g, 50% dispersion in oil, pre-washed with petroleum ether) in DMF(10 ml). On completion of the reaction, the reaction mixture was workedup as before to afford crude methyl2-[2-(3-(3-hydroxyphenoxy)pyridin-3-yl]-3-hydroxypropenoate. The productwas treated with potassium carbonate (0.31 g) and dimethyl sulphate(0.27 g) in DMF (10 ml) under the conditions described in Example 2 togive after standard work-up an oil. Chromatography on silica gel (eluentpetroleum ether - ether, 50:50) gave (E)-methyl2-[2-(3-hydroxyphenoxy)pyridin-3-yl]-3-methoxypropenoate as a whitesolid (0.35 g, 31%).

Melting point : 163°-165° C.; mass spectrum m/e 301 (M⁺).

Infrared max. 1665, 1663 cm⁻¹ : ¹ H NMR (CDCl₃) delta 3.68 (3H, s); 3.86(3H, s); 6.48 (1H); 6.54-6.6 (3H); 7.00-7.06 (1H); 7.12-7.20 (1H); 7.58(1H, s); 7.60-7.64 (1H); 8.08-8.12 (1H) ppm.

(E)-Methyl 2-[2-(3-hydroxyphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.1g, prepared as described above) was stirred with 3-nitrobenzenesulphonylchloride (0.074 g) and triethylamine (0.074 ml) in dry dichloromethane(3 ml) at room temperature. After one hour the reaction mixture wasapplied directly onto a silica gel column. Elution with petroleumether - ether (50:50) afforded the title compound as a white foamy solid(0.101 g, 63%).

Melting point : 49°-51° C.; mass spectrum m/e 486 (M⁺).

Infrared max. 1710, 1638 cm⁻¹ : ¹ H NMR (CDCl₃) delta 3.66 (3H,s), 3.85(3H,s); 6.77-6.83 (2H); 7.00-7.09 (2H); 7.29-7.31 (1H); 7.57 (1H, s);7.60-7.62 (1H); 7.71-7.78 (1H); 8.03-8.08 (1H) ppm.

EXAMPLE 4

This Example illustrates the preparation of (E)-methyl2-[2-(3-((4-nitrophenoxy)phenoxy)pyridin-3-yl]-3-methoxypropenoate(Compound No. 133 of Table I).

(E)-Methyl 2-[2-(3-hydroxyphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.3g; prepared as described in Example 3) and potassium carbonate (0.069 g)were heated together in DMF (5 ml) at 70° C. After 20 minutes,4-fluoronitrobenzene (0.141 g) and copper-bronze (cat.) were added andthe resulting mixture heated at 130° C. for 2 hours. GC analysisindicated the absence of starting material. The reaction mixture wasfiltered and then poured into water (70 ml). The resulting mixture wasextracted with ether (× 3). The combined ether extracts were dried,filtered and evaporated to give an orange oil. Chromatography on silicagel afforded the title compound as a white crystalline solid (0.266 g,64%).

Melting point : 102°-103° C.; mass spectrum m/e 422(M⁺).

Infrared max. 1700, 1626 cm⁻¹ : ¹ H NMR (CDCl₃) delta 3.64 (3H, s); 3.85(3H, s); 6.80-6.88 (2H); 6.94-7.10 (4H); 7.36-7.42 (1H); 7.59 (1H, s);7.60-7.64 (1H); 8.10-8.12 (1H); 8.16-8.22 (2H).

EXAMPLE 5

This Example illustrates the preparation of (E)-methyl2-[2-(3-pyrimidin-2-yloxy)phenoxy)pyridin-3-yl]-3-methoxypropenoate(Compound No. 22 of Table II).

(E)-Methyl 2-[2-(3-hydroxyphenoxy)pyridin-3-yl]-3-methoxypropenoate(0.67 g; prepared as described in Example 3) was heated at 80° C. withpotassium carbonate (0.154 g) in DMF (10 ml) under an atmosphere ofnitrogen. After 20 minutes 2-chloropyrimidine (0.253 g) andcopper-bronze (cat.) were added and the resultant mixture heated at 130°C. with stirring for 21/2 hours. GC analysis indicated the completion ofthe reaction. The reaction mixture was cooled, filtered and then pouredinto water. The aqueous phase was then extracted with ether (× 3). Thecombined ether layers were dried, filtered and evaporated to give ayellowish solid. Chromatography on silica gel (eluent ether - etheracetate, 2:1) gave the title compound as a white solid (0.308 g, 37%).

Melting point : 151°-153° C.; mass spectrum m/e 379(M⁺).

Infrared max. 1695, 1635 cm⁻¹ : ¹ H NMR (CDCl₃) delta 3.68 (3H,s ); 3.85(3H, s); 6.94-7.06 (5H); 7.38-7.43 (1H); 7.57 (1H, s); 7.62-7.66 (1H);8.11-8.15 (1H); 8.53-8.57 (2H) ppm.

EXAMPLE 6

This Example illustrates the preparation of (E)-methyl2-[2-(3-phenoxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (CompoundNo. 21 of Table I).

A mixture of 2-chloro-3-pyridinecarboxaldehyde (10.0 g), 3-hydroxybenzylalcohol (8.76 g); anhydrous potassium carbonate (4.88 g) in DMF (70 ml)was heated to reflux. After 3 hours, GC analysis showed that all of thealdehyde had been consumed. The reaction mixture was cooled and filteredand then poured into water. The resultant mixture was extracted withether (× 3) and the combined ether layers washed once with dilute sodiumhydroxide solution. The ether solution was then dried, filtered andevaporated to give a pale orange oil which crystallised on standing(9.13 g). To a solution of this product (6.24 g) and methylmethylsulphinylmethyl sulphide (3.38 g) in THF at room temperature undernitrogen was added dropwise Triton B (8 ml, 40% solution in methanol).After heating at reflux for 4 hours, the reaction mixture was cooled atroom temperature and dichloromethane (300 ml) was added. The resultantsolution was extracted with water (× 3). The dichloromethane layer wasdried, filtered and evaporated to give a dark orange oil (8.5 g) whichwas used directly in the next stage.

The dark organge oil (8.5 g, crude) was dissolved in methanolic hydrogenchloride (from methanol (150 ml) and acetyl chloride (15 ml)), stirredfor 3 hours and then left to stand over the weekend. The methanol wasremoved by evaporation and a saturated aqueous solution of sodiumbicarbonate was added. The mixture was extracted with ethyl acetate (×3) and the combined organic layers dried, filtered and evaporated togive a yellow oil. The oil was filtered through a plug of silica (eluentdichloromethane then ether).

Evaporation of the solvent afforded methyl2-(3-hydroxymethylphenoxy)-3-pyridinylacetate as a pale orange oil (4.04g, 88% pure by GC).

Infrared max. 3400, 1737 cm⁻¹.

The product was used in the next stage without further purification.

A solution of methyl 2-(3-hydroxymethylphenoxy)-3-pyridinylacetate (0.6g) and triethylamine (0.45 ml) in dichloromethane (2 ml) was addeddropwise over 20 minutes to a stirred solution of mesyl chloride (0.26ml) in dichloromethane (6 ml) at ca. 5° C. The mixture was stirred at 5°C. for 30 minutes, warmed to room temperature and then allowed to standover the weekend. GC analysis of an aliquot indicated complete reaction.The reaction mixture was stirred with brine for 30 minutes and then theorganic layer was dried, filtered and evaporated to give methyl2-(3-chloromethylphenoxy)-3-pyridinylacetate as a pale yellow oil (0.55g) which was used directly.

Infrared max. 1738 cm⁻¹ ; mass spectrum m/e 291 (M⁺).

¹ H NMR (CDCl₃) : inter alia delta 3.69 (3H, s); 3.77 (2H, s); 4.60 (2H,s).

Phenol (0.16 g) and potassium carbonate (0.12 g) were stirred togetherin DMF (6 ml) under nitrogen at room temperature. After 20 minutes, asolution of methyl 2-(3-chloromethylphenoxy)-3-pyridinylacetate (0.5 g)in DMF was added and stirring continued. Copper-bronze (cat.) was addedand the reaction mixture heated at 100° C. for a total of 5 hours. GCanalysis indicated complete reaction. The reaction mixture was cooledand filtered, and then poured into water (50 ml). The aqueous mixturewas extracted with ether (× 3) and the combined extracts washed withdilute sodium hydroxide solution. The ether solution was the dried,filtered and evaporated to give methyl2-(3-phenoxymethylphenoxy)-3-pyridinylacetate as a yellow oil (0.35 g,59%), mass spectrum m/e 349 (M⁺); ¹ H NMR (CDCl₃) inter alia delta 3.69(3H, s); 3.76 (2H, s); 5.07 (2H, s) ppm, contained with traces of DMF.In a separate experiment, the chloromethyl compound (2.73 g, prepared asabove) yielded a further 2.00 g of methyl2-(3-phenoxymethylphenoxy)-3-pyridinylacetate.

A solution of methyl 2-(3-phenoxymethylphenoxy)-3-pyridinylacetate (2.35g) and methyl formate (6.2 ml) in DMF was added to a suspension ofsodium hydride (0.64 g, 50% dispersion in oil, pre-washed with petroleumether) in DMF (25 ml) under the same conditions described in the finalstage of Example 1. Standard work-up yielded crude methyl2-[2-(3-phenoxymethylphenoxy)pyridin-3-yl]-3-hydroxpropenoate which wastreated directly with potassium carbonate (1.85 g) and dimethylsulphate(0.63 ml) in DMF (17 ml). Standard work-up and chromatography on silicagel (eluent petroleum ether-ether, 50:50) afforded the title compound asa white gum (0.53 g), 1638 cm⁻¹ ; ¹ H NMR as in Table V.

EXAMPLE 7

This Example illustrates the preparation of (E)-methyl2-[2-(3-(2-methoxyphenoxy)phenoxy)pyridin-3-yl]-3-methoxypropenoate(Compound No. 128 of Table I).

To an ice-cold stirred suspension of petrol-washed sodium hydride (1.04g, 50% dispersion in oil, 22 mmol) in DMF (16 ml) was added a solutionof methyl 2-chloropyrid-3-ylacetate (2 g, 11 mmol) and methyl formate(12.95 g, 0.22 mol) in DMF (8 ml). The reaction mixture was allowed towarm to room temperature and stirring continued until tlc analysisshowed that no starting material remained (ca. 3 hours). The reactionmixture was poured into water and then acidified with dilutehydrochloric acid. The solution was extracted repeatedly with ether andthe combined extracts dried, filtered and evaporated. The residue wasredissolved in DMF and then treated with dimethyl sulphate (1.32 g, 10.5mmol) and anhydrous potassium carbonate (1.52 g, 11 mmol) at roomtemperature.

The reaction mixture was stirred for 2 hours, diluted with water andthen repeatedly extracted with ether. The combined ether extracts weredried, filtered and evaporated to afford a yellow oil. Chromatrographyon silica (eluent petrol-ether, 50:50) gave (E)-methyl2-(2-chloropyrid-3-yl)-3-methoxypropenoate as a white waxy solid (0.9 g,36%).

Melting point : 39°-40° C.

Infrared max. : 1711, 1638 cm⁻¹.

¹ H NMR delta : 3.74 (3H, s), 3.89 (3H, s), 7.21-7.26 (1H), 7.55-7.57(1H), 7.60 (1H, s), 8.32-8.36 (1H).

(E)-Methyl 2-(2-chloropyridin-3-yl)-3-methoxypropenoate (0.227 g),3-(2-methoxyphenoxy)phenol (0.255 g), anhydrous potassium carbonate(0.069 g), copper-bronze (cat.) and copper (I) chloride (cat.) wereheated together at ca. 170° C. for 3 hours under nitrogen. The reactionmixture was cooled and then diluted with a small amount ofdichloromethane. The resulting mixture was applied directly to a columnof silica gel and chromatographed (eluent petroleum ether-ether, 1:1) toafford the title compound as a pale brown oil (0.023 g, 6%), massspectrum m/e 407 (M⁺) ¹ H NMR (CDCl₃) as in Table V.

EXAMPLE 8

This Example illustrates the preparation of (E)-methyl2-[2-(3-(alpha-hydroxybenzylphenoxy)pyridin-3-yl]-3-methoxypropenoate(Compound No. 380 of Table I).

To a stirred suspension of sodium hydride (1.056 g, 50% dispersion inoil, pre-washed with petroleum ether) in dry DMF (15 ml) at 0°-5° C. wasadded dropwise over 5 minutes a solution containing methyl2-(3-hydroxymethylphenoxy)pyridin-3-ylacetate (2.0 g) and methyl formate(9 ml) in DMF (effervescence). After the addition was complete, thereaction mixture was allowed to warm to room temperature. After stirringfor a further 3 hours, the reaction mixture was carefully poured intowater, neutralised with 2N hydrochloric acid and then extractedthoroughly with ether (× 6). The combined ether layers were dried,filtered and evaporated to afford a crude residue which was used withoutfurther purification. The residue was dissolved in DMF (10 ml) and thentreated with potassium carbonate (0.60 g) and dimethyl sulphate (0.64g). Standard work-up and chromatography on silica gel (eluent petroleumether-ether, 1:1) afforded (E)-methyl2-[2-(3hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.35 g,15%); mass spectrum m/e 315 (M⁺).

Infrared max. : 3396 (br.), 1708, 1638 cm⁻¹.

¹ H NMR (CDCl₃) delta : 1.63 (br. 0--H); 3.69 (3H, s); 3.85 (3H, s);4.69 (2H, s); 6.98-7.05 (2H, m); 7.09-7.17 (2H, m); 7.31-7.37 (1H, m);7.57 (1H, s); 7.61-7.63 (1H, m); 8.07-8.11 (1H, m) ppm.

(This compound can be converted to (E)-methyl2-[2-(3-chloromethyl)pyridin-3-yl]-3-methoxypropenoate by treatment withmesyl chloride and triethylamine as described for methyl2-(3-chloromethylphenoxy)pyridin-3-ylacetate in Example 6).

To a stirred solution of (E)-methyl2-[2-(3-hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.250 g)in dichloromethane (5 ml) at room temperature was added pyridiniumdichromate (0.414 g). After stirring for 3 hours, GC analysis of analiquot indicated the absence of starting material. Water was added andstirring continued for 10 minutes. The reaction mixture was filtered(filter washed through with water (5 ml) and dichloromethane (5 ml)) andthen further diluted with dichloromethane (5 ml). The organic layer wasseparated and the aqueous phase further extracted with dichloromethane(× 3). The combined organic layers were dried, filtered and evaporatedto give a dark yellow oil. Chromatography on silica gel (eluentether-petroleum ether, 7:3) afforded (E)-methyl2-[2-(3-formylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.136 g, 55%)as a white solid.

Melting point : 84°-86° C.

Infrared max. : 1705, 1698, 1633 cm⁻¹.

¹ H NMR (CDCl₃) delta : 3.64 (3H, s); 3.85 (3H, s); 7.04-7.08 (1H, m);7.36-7.40 (1H, m); 7.59 (1H, s); 7.50-7.70 (4H, m); 8.09-8.11 (1H, m);10.00 (1H, s).

To a stirred solution of (E)-methyl2-[2-(3-formylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.115 g) inether (3 ml, containing a few drops of THF) under nitrogen at -5° to-10° C. was added dropwise over 15 minutes phenylmagnesium bromide (1equiv. in 2 ml ether). After a further 20 minutes, GC analysis of analiquot indicated the presence of starting material (34%). A further 0.2equivalents of phenylmagnesium bromide was added and stirring continuedfor 10 minutes. GC analysis of an aliquot showed the absence of startingmaterial. The reaction mixture was poured into ice and a few drops of15% sulphuric acid were added. The ether layer was separated and theaqueous residue extracted with ether (× 2). The combined organicextracts were dried, filtered and evaporated to give a yellow oil.Chromatography on silica gel (eluent ether-petroleum ether, 6:4) gavethe title compound as the major product (white oil, 0.059 g, 40%); massspectrum m/e 391 (M⁺).

Infrared max. : 3420, 1707, 1637 cm⁻¹.

¹ H NMR (CDCl₃) delta : 2.35 (1H, br. s); 3.63 (3H, s); 3.81 (3H, s);5.83 (1H, s); 6.96-7.40 (10H, m); 7.55 (1H, s); 7.58-7.62 (1H, m);8.06-8.09 (1H, m) ppm.

The following are examples of compositions suitable for agricultural andhorticultural purposes which can be formulated from the compounds of theinvention. Such compositions form another aspect of the invention.Percentages are by weight.

EXAMPLE 9

An emulsifiable concentrate is made up by mixing and stirring theingredients until all are dissolved.

    ______________________________________                                        Compound No. 446 of Table I                                                                          10%                                                    Benzyl alcohol         30%                                                    Calcium dodecylbenzenesulphonate                                                                      5%                                                    Nonylphenolethoxylate (13 mole                                                                       10%                                                    ethylene oxide)                                                               Alkyl benzenes         45%                                                    ______________________________________                                    

EXAMPLE 10

The active ingredient is dissolved in methylene dichloride and theresultant liquid sprayed on to the granules of attapulgite clay. Thesolvent is then allowed to evaporate to produce a granular composition.

    ______________________________________                                        Compound No. 446 of Table I                                                                         5%                                                      Attapulgite granules 95%                                                      ______________________________________                                    

EXAMPLE 11

A composition suitable for use as a seed dressing is prepared bygrinding and mixing the three ingredients.

    ______________________________________                                        Compound No. 446 of Table I                                                                        50%                                                      Mineral oil           2%                                                      China clay           48%                                                      ______________________________________                                    

EXAMPLE 12

A dustable powder is prepared by grinding and mixing the activeingredient with talc.

    ______________________________________                                        Compound No. 446 of Table I                                                                         5%                                                      Talc                 95%                                                      ______________________________________                                    

EXAMPLE 13

A suspension concentrate is prepared by ball milling the ingredients toform an aqueous suspension of the ground mixture with water.

    ______________________________________                                        Compound No. 446 of Table I                                                                        40%                                                      Sodium lignosulphonate                                                                             10%                                                      Bentonite clay        1%                                                      Water                49%                                                      ______________________________________                                    

This formulation can be used as a spray by diluting into water orapplied directly to seed.

EXAMPLE 14

A wettable powder formulation is made by mixing together and grindingthe ingredients until all are thoroughly mixed.

    ______________________________________                                        Compound No. 446 of Table I                                                                        25%                                                      Sodium lauryl sulphate                                                                              2%                                                      Sodium lignosulphonate                                                                              5%                                                      Silica               25%                                                      China clay           43%                                                      ______________________________________                                    

EXAMPLE 15

The compounds were tested against a variety of foliar fungal diseases ofplants. The technique employed was as follows.

The plants were grown in John Innes Potting Compost (No 1 or 2) in 4 cmdiameter minipots. The test compounds were formulated either by beadmilling with aqueous Dispersol T or as a solution in acetone oracetone/ethanol which was diluted to the required concentrationimmediately before use. For the foliage diseases, the formulations (100ppm active ingredient) were sprayed onto the foliage and applied to theroots of the plants in the soil. The sprays were applied to maximumretention and the root drenches to a final concentration equivalent toapproximately 40 ppm a.i./dry soil. Tween 20, to give a finalconcentration of 0.05%, was added when the sprays were applied tocereals.

For most of the tests the compound was applied to the soil (roots) andto the foliage (by spraying) one or two days before the plant wasinoculated with the disease. An exception was the test on Erysiphegraminis in which the plants were inoculated 24 hours before treatment.Foliar pathogens were applied by spray as spore suspensions onto theleaves of test plants. After inoculation, the plants were put into anappropriate environment to allow infection to proceed and then incubateuntil the disease was ready for assessment. The period betweeninoculation and assessment varied from four to fourteen days accordingto the disease and environment.

The disease control was recorded by the following grading :

                                      TABLE VI                                    __________________________________________________________________________                      ERYSIPHE       PYRI-           PLASMO-                                                                              PHYTO-                COM-      PUCCINIA                                                                              GRAMINIS                                                                             VENTURIA                                                                              CULARIA                                                                             CERCOSPORA                                                                              PARA   PHTHORA               POUND                                                                              TABLE                                                                              RECONDITA                                                                             HORDEI INAEQUALIS                                                                            ORYZAE                                                                              ARACHIDICOLA                                                                            VITICOLA                                                                             INFESTANS             NO.  NO.  (WHEAT) (BARLEY)                                                                             (APPLE) (RICE)                                                                              (PEANUT)  (VINE) (TOMATO)              __________________________________________________________________________     21  I    4       4      4       4     4         4      2                      23  I    4       4      4       3     4         4      4                     119  I    4       3      4       3     4         4      4                     128  I    4a      2a     4a      3a    4a        4a     3a                    131  I    4       4      4       4     4         4      4                     133  I    4       3      4       2     3         4      0                     134  I    4a      4a     4a      4a    4a        4a     4a                    212  I    4       3      4       4     4         4      4                     296  I    3a      0a     2a      1a    0a        4a     3a                    376  I    3       4      4       4     4         4      2                     381  I    3       0      4       0     0         4      2                     446  I    4       4      4       4     3         4      4                     447  I    4       3      3       0     4         4      4                      22  II   4       4      4       4     3         4      0                      89  II   4       4      3       --    3         4      4                      97  II   3       4      4             2         4      3                     106  II   4       4      4       --    4         4      4                     320  II   3       4      4             3         4      3                     __________________________________________________________________________     a = 25 ppm foliar spray only                                                  -- = no result                                                           

We claim:
 1. A fungicidal compound of the formula (I): ##STR27## or astereoisomer thereof, wherein A, B and E, which are the same ordifferent, are H, halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl,phenoxy, nitro or cyano; K is oxygen or sulphur; X is O; and Z is arylsubstituted with one or more of halo, hydroxy, mercapto, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₂₋₄ alkenyloxy, C₂₋₄alkynyloxy, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio,hydroxy(C₁₋₄)alkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, aryl, pyridinyl or pyrimidinyl, aryloxy,aryl(C₁₋₄)alkyl, aryl(C₁₋₄)alkyl in which the alkyl moiety issubstituted with hydroxy, pyrimidinyl(C₁₋₄)alkyl orpyridinyl(C₁₋₄)alkyl, aryl(C₂₋₄)alkenyl, pyrimidinyl(C₂₋₄)alkenyl orpyridinyl(C₂₋₄)alkenyl, aryl(C₁₋₄)alkoxy, pyrimidinyl(C₁₋₄)alkoxy orpyridinyl(C₁₋₄)alkoxy, aryloxy(C₁₋₄)alkyl, pyrimidinyloxy(C₁₋₄)alkyl orpyridinyloxy(C₂₋₄)alkyl, carbacyloxy, cyano, thiocyanato, nitro,--NR'R", --NHCOR', --NHCONR'R", --CONR'R", --COOR' , --OSO₂ R', --SO₂R', --COR', --CR═NR" or --N═CR'R" in which R' and R" are independentlyhydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenyl or benzyl, or phenyl or benzyl substitutedwith halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; the aryl or pyrimidinyl orpyridinyl rings of any of the foregoing substituents being optionallysubstituted with one or more of halo, hydroxy, mercapto, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₂₋₄ alkenyloxy, C₂₋₄alkynyloxy, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio,hydroxy(C₁₋₄)alkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, alkanoyloxy, benzoyloxy, cyano, thiocyanato,nitro, --NR'R", --NHCOR', --NHCONR'R", --CONR'R", --COOR', --OSO₂ R',--SO₂ R', --COR', --CR'═NR" or --N═CR'R" in which R' and R" have themeanings given above provided that Z is not phenyl substituted only withC₁₋₄ alkyl.
 2. A fungicidal compound of the formula (Ia): ##STR28##wherein X is O; A is H, hydroxy, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy,trifluoromethyl, nitro, cyano, acetyl or phenoxy; B and E are H or halo;D is hydroxy, halo, C₁₋₄ alkoxy, nitro, cyano, halo(C₁₋₄)alkyl,halo(C₁₋₄)alkoxy, phenyl, phenoxy, NHCOR⁶, NHSO₂ R⁶, NR⁷ R⁸, CO₂ R⁷,wherein R⁶ is C₁₋₄ alkyl or phenyl and R⁷ and R⁸ are independently H orC₁₋₄ alkyl, or CH₃ O₂ C.C═CH.OCH₃ ; and G is H, halo, C₁₋₄ alkyl, C₁₋₄alkoxy or nitro; or D and G, when they are adjacent, join to form abenzene or pyridine ring.
 3. A compound according to claim 2 wherein Xis O; D is halo, C₁₋₄ alkoxy, nitro, cyano or amino; and A, B, E and Gare all H.
 4. A fungicidal composition comprising a fungicidallyeffective amount of a compound according to claim 1 and a fungicidallyacceptable carrier or diluent therefor.
 5. A method of combating fungiwhich comprises applying to plants, to the seeds of plants or to thelocus of the plants or seeds, a compound according to claim 1 or acomposition according to claim 1.